東北大学研究者紹介

研究者詳細

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日本語 English

顔写真

コシバ　セイゾウ

小柴　生造

Seizo Koshiba

所属

高等研究機構未来型医療創成センター　研究部

職名

教授

学位

博士（理学）（東京大学）
修士（理学）（東京大学）

researchmap

https://researchmap.jp/7000006944

J-GLOBAL ID

201401080315058530

経歴 2

2020年3月～継続中

東北大学　未来型医療創成センター　教授
2017年5月～継続中

東北大学　東北メディカル・メガバンク機構　教授

研究キーワード 6

クライオ電子顕微鏡
メタボローム
核磁気共鳴
構造解析
オミックス
生化学

研究分野 3

ライフサイエンス / 構造生物化学 /
ライフサイエンス / 医化学 /
ライフサイエンス / 機能生物化学 /

論文 133

Exploring the association between human breast milk lipids and early adiposity rebound in children: A case-control study. 国際誌

Kento Sawane, Ippei Takahashi, Mami Ishikuro, Hiroko Takumi, Masatsugu Orui, Aoi Noda, Genki Shinoda, Hisashi Ohseto, Tomomi Onuma, Fumihiko Ueno, Keiko Murakami, Naoko Higuchi, Takashi Furuyashiki, Tomohiro Nakamura, Seizo Koshiba, Kinuko Ohneda, Kazuki Kumada, Soichi Ogishima, Atsushi Hozawa, Junichi Sugawara, Shinichi Kuriyama, Taku Obara

Nutrition (Burbank, Los Angeles County, Calif.)　135　112739-112739　2025年3月8日

DOI： 10.1016/j.nut.2025.112739 　

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OBJECTIVES: Adiposity rebound (AR) corresponds to the start of the second rise in the body mass index curve during infant growth. Early AR (before age 5) confers increased risk of adiposity and metabolic disorders but is less likely to occur in breastfed infants. Although lipids in breast milk are important in child growth, information is limited regarding which lipids are involved in AR. The object of this study was to explore the association between breast milk lipids and AR status in children. METHODS: We designed a case-control study of 184 mother-child pairs (AR cases: n = 93; controls: n = 91) included from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Breast milk was collected 1 month postpartum and comprehensive lipid analysis was performed. Partial least square-discriminant analysis was used to explore candidate lipids, and multivariable logistic regression analysis was used to evaluate associations with the AR status of children. RESULTS: We detected 667 lipid molecules in 12 lipid classes in breast milk. Partial least square-discriminant analysis revealed the association of fatty acid-hydroxy fatty acid (FAHFA) and cholesterol ester (ChE) with AR status. Multivariable logistic regression analysis showed that in pairs with exclusive breastfeeding at 1 month postpartum, FAHFA (odds ratio 1.57 [95% confidence interval, 1.06-2.32]) was positively associated with early AR, and ChE (odds ratio 0.55 [95% confidence interval, 0.36-0.86]) was negatively associated. CONCLUSIONS: Breast milk lipids (FAHFA, ChE) associated with the AR status of children, indicating the potential to regulate a child's adiposity and possible metabolic disorders in adulthood.
Association Between Human Milk Oligosaccharides and Early Adiposity Rebound in Children: A Case-Control Study of the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. 国際誌

Kento Sawane, Ippei Takahashi, Mami Ishikuro, Hiroko Takumi, Masatsugu Orui, Aoi Noda, Genki Shinoda, Hisashi Ohseto, Tomomi Onuma, Fumihiko Ueno, Keiko Murakami, Naoko Higuchi, Tomoko Tanaka, Takashi Furuyashiki, Tomohiro Nakamura, Seizo Koshiba, Kinuko Ohneda, Kazuki Kumada, Soichi Ogishima, Atsushi Hozawa, Junichi Sugawara, Shinichi Kuriyama, Taku Obara

The Journal of nutrition　2025年3月7日

DOI： 10.1016/j.tjnut.2025.02.024 　

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BACKGROUND: Adiposity rebound (AR) is the point when the body mass index (BMI) begins to rise again during early childhood. Early AR (before age 5) is associated with a higher risk of lifelong obesity and metabolic disorders and may be influenced by breastfeeding. Although human milk oligosaccharides (HMOs) in breast milk are crucial for child growth, their association with AR status has not been studied. OBJECTIVE: To explore breast milk HMO compositions and molecules associated with AR status in children. METHODS: In this case-control study, we included 184 mother-child pairs from the Tohoku Medical Megabank Project Birth and Three-Generation (TMM BirThree) Cohort Study (93 AR cases, 91 controls). Breast milk was collected 1 month postpartum, and the concentration of 15 HMO molecules and alpha-diversity index (Inverse Simpson index) were quantified. Wilcoxon's rank-sum test and partial least squares-discriminant analysis (PLS-DA) identified candidate HMOs, and multivariable logistic regression analysis evaluated associations between candidate HMOs and AR status. Analyses were stratified by maternal secretor status (secretor or non-secretor). RESULTS: In secretor mothers, multivariable logistic regression showed that the Inverse Simpson index (OR, 0.54 [95% CI, 0.36-0.82]), sum of sialic acid-bound HMOs (0.61 [0.41-0.91]), and 3'-sialyllactose (0.67 [0.46-0.98]) were inversely associated with early AR in a fully adjusted model. A trend of interaction between sialyl-lacto-N-tetraose a (LSTa) and maternal secretor status on AR was observed in a fully adjusted model (P-value for interaction = 0.051). CONCLUSIONS: Alpha diversity, sialic acid-bound HMOs, and 3'SL may be involved in inhibiting AR in children of secretor mothers, and a trend of interactive effect of LSTa among maternal secretor status on AR was indicated. These findings offer novel perspectives on the associations between breastfeeding and a child's adiposity as well as potential metabolic disorders later in life. REGISTRY NUMBER/WEBSITE: https://www.umin.ac.jp/ (trial registration number: UMIN000047160).
Histological and genetic features and therapeutic responses of lung cancers explored via the global analysis of their metabolome profile

Daisuke Narita, Eiji Hishinuma, Risa Ebina-Shibuya, Eisaku Miyauchi, Naomi Matsukawa, Ikuko N. Motoike, Kengo Kinoshita, Seizo Koshiba, Yoko Tsukita, Hirotsugu Notsuda, Nozomu Kimura, Ryota Saito, Hisatoshi Sugiura

Lung Cancer　108082-108082　2025年1月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.lungcan.2025.108082 　

ISSN：0169-5002
Absolute quantification of eight human milk oligosaccharides in breast milk to evaluate their concentration profiles and associations with infants' neurodevelopmental outcomes. 国際誌

Keigo Sato, Yoshitaka Nakamura, Kazuhito Fujiyama, Kinuko Ohneda, Takahiro Nobukuni, Soichi Ogishima, Satoshi Mizuno, Seizo Koshiba, Shinichi Kuriyama, Shinji Jinno

Journal of food science　89　(12)　10152-10170　2024年12月

DOI： 10.1111/1750-3841.17597 　

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Human milk oligosaccharides (HMOs) have been positively associated with child neurodevelopment in some cohort studies. However, there is a lack of consistency in the association between HMOs and benefits to infants' brains. Moreover, the quantification methods for HMOs have not yet been standardized. In this study, we developed a quantification method for evaluating eight HMOs (2'-fucosyllactose [2'-FL], 3'-fucosyllactose [3'-FL], 3'-sialyllactose [3'-SL], 6'-sialyllactose [6'-SL], lactosialyltetrasaccharide a [LSTa], lactosialyltetrasaccharide b [LSTb], lactosialyltetrasaccharide c [LSTc], and disialyllacto-N-tetraose [DSLNT]) in breast milk. After validating the method, we applied it to 1-month breast milk samples (n = 150) from the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study to assess HMO profiles in breast milk and their possible association with changes in head circumference z-score (ΔHCZ) and neurodevelopmental scores of children (as measured by the Ages and Stages Questionnaire, Third Edition). The validation demonstrated that the method had relative standard deviation ≤ 12.7% of precision and 79.5-110.9% of accuracy. Using this method, eight HMO levels (2'-FL, 0-4.74 mg/mL; 3'-FL, 0.02-1.52 mg/mL; 3'-SL, 0.07-0.32 mg/mL; 6'-SL, 0.01-0.70 mg/mL; LSTa, 0.002-0.043 mg/mL; LSTb, 0.02-0.31 mg/mL; LSTc, 0.001-0.47 mg/mL; and DSLNT, 0.09-0.71 mg/mL [min-max, all participants]) and the ratio of low secretors (16.0%) in the Japanese cohort were obtained. The obtained HMO levels in breast milk were subjected to multivariate analysis to screen for HMOs showing a positive association with ΔHCZ and neurodevelopmental scores. The results proposed that ΔHCZ was positively associated with LSTb and 2'-FL levels, whereas neurodevelopmental scores were positively associated with 2'-FL levels (among all participants) and 3'-SL and DSLNT levels (among secretor participants). This study showed that the developed method provides HMO profiles in Japanese breast milk, as well as additional information on the associations between specific HMOs and neurodevelopment, reinforcing the sum of evidence for the role of HMOs in the brain.
Metabolomic Profiling of Open-Angle Glaucoma Etiologic Endotypes: Tohoku Multi-Omics Glaucoma Study. 国際誌

Akiko Hanyuda, Yoshihiko Raita, Takahiro Ninomiya, Kazuki Hashimoto, Naoko Takada, Kota Sato, Jin Inoue, Seizo Koshiba, Gen Tamiya, Akira Narita, Masato Akiyama, Kazuko Omodaka, Satoru Tsuda, Yu Yokoyama, Noriko Himori, Yasuko Yamamoto, Takazumi Taniguchi, Kazuno Negishi, Toru Nakazawa

Investigative ophthalmology & visual science　65　(13)　44-44　2024年11月4日

DOI： 10.1167/iovs.65.13.44 　

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PURPOSE: The purpose of this study was to investigate biologically meaningful endotypes of open-angle glaucoma (OAG) by applying unsupervised machine learning to plasma metabolites. METHODS: This retrospective longitudinal cohort study enrolled consecutive patients aged ≥20 years with OAG at Tohoku University Hospital from January 2017 to January 2020. OAG was confirmed based on comprehensive ophthalmic examinations. Among the 523 patients with OAG with available clinical metabolomic data, 173 patients were longitudinally followed up for ≥2 years, with available data from ≥5 reliable visual field (VF) tests without glaucoma surgery. We collected fasting blood samples and clinical data at enrollment and nuclear magnetic resonance spectroscopy to profile 45 plasma metabolites in a targeted approach. After computing a distance matrix of preprocessed metabolites with Pearson distance, gap statistics determined the optimal number of OAG endotypes. Its risk factors, clinical presentations, metabolomic profiles, and progression rate of sector-based VF loss were compared across endotypes. RESULTS: Five distinct OAG endotypes were identified. The highest-risk endotype (endotype B) showed a significant faster progression of central VF loss (P = 0.007). Compared with patients with other endotypes, those with endotype B were more likely to have a high prevalence of dyslipidemia, cold extremities, oxidative stress, and low OAG genetic risk scores. Pathway analysis of metabolomic profiles implicated altered fatty acid and ketone body metabolism in this endotype, with 34 differentially enriched pathways (false discovery rate [FDR] < 0.05). CONCLUSIONS: Integrated metabolomic profiles identified five distinct etiologic endotypes of OAG, suggesting pathological mechanisms related with a high-risk group of central vision loss progression in the Japanese population.
Association of olfactory and cognitive function test scores with hippocampal and amygdalar grey matter volume: a cross-sectional study. 国際誌

Shuichi Sato, Takao Imaeda, Shunji Mugikura, Naoko Mori, Masaki Takanashi, Kazumi Hayakawa, Tomo Saito, Makiko Taira, Akira Narita, Mana Kogure, Ippei Chiba, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Ryosuke Ishiwata, Tomohiro Nakamura, Ikuko N Motoike, Naoki Nakaya, Seizo Koshiba, Kengo Kinoshita, Shinichi Kuriyama, Soichi Ogishima, Fuji Nagami, Nobuo Fuse, Atsushi Hozawa

Scientific reports　14　(1)　19138-19138　2024年8月19日

DOI： 10.1038/s41598-024-69726-4 　

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Few population-based studies including younger adults have examined the potential of olfactory function tests to capture the degree of atrophy in memory-associated brain regions, which cannot be adequately explained by cognitive function tests screening for cognitive impairment. This population-based study investigated associations between high-resolution olfactory test data with few odours and grey matter volumes (GMVs) of the left and right hippocampi, amygdala, parahippocampi, and olfactory cortex, while accounting for differences in cognitive decline, in 1444 participants (aged 31-91 years). Regression analyses included intracranial volume (ICV)-normalised GMVs of eight memory-related regions as objective variables and age, sex, education duration, smoking history, olfaction test score, and the Montreal Cognitive Assessment-Japanese version (MoCA-J) score as explanatory variables. Significant relationships were found between olfactory test scores and ICV-normalised GMVs of the left and right hippocampi and left amygdala (p = 0.020, 0.024, and 0.028, respectively), adjusting for the MoCA-J score. The olfactory test score was significantly related to the right amygdalar GMV (p = 0.020) in older adults (age ≥ 65 years). These associations remained significant after applying Benjamini-Hochberg multiple testing correction (false discovery rate < 0.1). Therefore, olfactory and cognitive function tests may efficiently capture the degree of atrophy in the hippocampi and amygdala, especially in older adults.
Mutations of CYP1B1 and FOXC1 genes for childhood glaucoma in Japanese individuals.

Nobuo Fuse, Masae Kimura, Ai Shimizu, Seizo Koshiba, Teruhiko Hamanaka, Makoto Nakamura, Nobuo Ishida, Hiroshi Sakai, Yoko Ikeda, Kazuhiko Mori, Atsushi Endo, Masao Nagasaki, Fumiki Katsuoka, Jun Yasuda, Yoichi Matsubara, Toru Nakazawa, Masayuki Yamamoto

Japanese journal of ophthalmology　2024年8月19日

DOI： 10.1007/s10384-024-01103-0 　

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PURPOSE: To explore the frequency and positions of genetic mutations in CYP1B1 and FOXC1 in a Japanese population. STUDY DESIGN: Molecular genetic analysis. METHODS: Genomic DNA was extracted from 31 Japanese patients with childhood glaucoma (CG) from 29 families. We examined the CYP1B, FOXC1, and MYOC genes using Sanger sequencing and whole-exome sequencing (WES). RESULTS: For CYP1B1, we identified 9 families that harbored novel mutations, p.A202T, p.D274E, p.Q340*, and p.V420G; the remaining mutations had been previously reported. When mapped to the CYP1B1 protein structure, all mutations appeared to influence the enzymatic activity of CYP1B1 by provoking structural deformity. Five patients were homozygotes or compound heterozygotes, supporting the recessive inheritance of the CYP1B1 mutations in CG. In contrast, four patients were heterozygous for the CYP1B1 mutation, suggesting the presence of regulatory region mutations or strong modifiers. For the FOXC1 gene, we identified 3 novel mutations, p.Q23fs, p.Q70R, and p.E163*, all of which were identified in a heterozygous state. No mutation was found in the MYOC gene in these CG patients. All individuals with CYP1B1 and FOXC1 mutations were severely affected by early-onset CG. In the CYP1B1-, FOXC1-, and MYOC-negative families, we also searched for variants in the other candidate genes reported for CG through WES, but could not find any mutations in these genes. CONCLUSIONS: Our analyses of 29 CG families revealed 9 families with point mutations in the CYP1B1 gene, and four of those patients appeared to be heterozygotes, suggesting the presence of complex pathogenic mechanisms. FOXC1 appears to be another major causal gene of CG, indicating that panel sequencing of CYP1B1 and FOXC1 will be useful for diagnosis of CG in Japanese individuals.
Identifying critical age and gender-based metabolomic shifts in a Japanese population of the Tohoku Medical Megabank cohort. 国際誌

Miyuki Sakurai, Ikuko N Motoike, Eiji Hishinuma, Yuichi Aoki, Shu Tadaka, Mana Kogure, Masatsugu Orui, Mami Ishikuro, Taku Obara, Naoki Nakaya, Kazuki Kumada, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

Scientific reports　14　(1)　15681-15681　2024年7月8日

DOI： 10.1038/s41598-024-66180-0 　

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Understanding the physiological changes associated with aging and the associated disease risks is essential to establish biomarkers as indicators of biological aging. This study used the NMR-measured plasma metabolome to calculate age-specific metabolite indices. In doing so, the scope of the study was deliberately simplified to capture general trends and insights into age-related changes in metabolic patterns. In addition, changes in metabolite concentrations with age were examined in detail, with the period from 55-59 to 60-64 years being a period of significant metabolic change, particularly in men, and from 45-49 to 50-54 years in females. These results illustrate the different variations in metabolite concentrations by sex and provide new insights into the relationship between age and metabolic diseases.
A principal component analysis of metabolome and cognitive decline among Japanese older adults: cross-sectional analysis using Tohoku Medical Megabank Cohort Study.

Sakura Kiuchi, Kumi Nakaya, Upul Cooray, Kenji Takeuchi, Ikuko N Motoike, Naoki Nakaya, Yasuyuki Taki, Seizo Koshiba, Shunji Mugikura, Ken Osaka, Atsushi Hozawa

Journal of epidemiology　2024年7月6日

DOI： 10.2188/jea.JE20240099 　

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BackgroundDementia is the leading cause of disability and imposes a significant burden on society. Previous studies have suggested an association between metabolites and cognitive decline. Although the metabolite composition differs between Western and Asian populations, studies targeting Asian populations remain scarce.MethodsThis cross-sectional study used data from a cohort survey of community-dwelling older adults aged ≥ 60 years living in Miyagi, Japan, conducted by Tohoku Medical Megabank Organization between 2013 and 2016. Forty-three metabolite variables quantified using nuclear magnetic resonance spectroscopy were used as explanatory variables. Dependent variable was the presence of cognitive decline (≤ 23 points), assessed by the Mini-Mental State Examination. Principal component (PC) analysis was performed to reduce the dimensionality of metabolite variables, followed by logistic regression analysis to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cognitive decline.ResultsA total of 2,940 participants were included (men: 49.0%, mean age: 67.6 years). Among them, 1.9% showed cognitive decline. The first 12 PC components (PC1-PC12) accounted for 71.7% of the total variance. Multivariate analysis showed that PC1, which mainly represented essential amino acids, was associated with lower odds of cognitive decline (OR = 0.89; 95% CI, 0.80-0.98). PC2, which mainly included ketone bodies, was associated with cognitive decline (OR = 1.29; 95% CI, 1.11-1.51). PC3, which included amino acids, was associated with lower odds of cognitive decline (OR = 0.81; 95% CI, 0.66-0.99).ConclusionAmino acids are protectively associated with cognitive decline, whereas ketone metabolites are associated with higher odds of cognitive decline.
血中代謝産物に着目した経時的リキッドバイオプシーによる進行再発卵巣癌モニタリング法の開発

重田昌吾, 菱沼英史, 島田宗昭, 渋谷祐介, 湊敬道, 安田純, 湊純子, 橋本千明, 石橋ますみ, 小柴生造, 徳永英樹, 八重樫伸生

日本婦人科腫瘍学会学術講演会プログラム・抄録集　66回　272-272　2024年7月
出版者・発行元： (公社)日本婦人科腫瘍学会
The drug-specific properties of hypoxia-inducible factor-prolyl hydroxylase inhibitors in mice reveal a significant contribution of the kidney compared to the liver to erythropoietin induction

Taku Nakai, Daisuke Saigusa, Koichiro Kato, Tomoko Fukuuchi, Seizo Koshiba, Masayuki Yamamoto, Norio Suzuki

Life Sciences　346　122641-122641　2024年6月
出版者・発行元： Elsevier BV
DOI： 10.1016/j.lfs.2024.122641 　

ISSN：0024-3205
Dietary habits and plasma lipid concentrations in a general Japanese population. 国際誌

Mitsuharu Sato, Eiji Hishinuma, Naomi Matsukawa, Yoshiko Shima, Daisuke Saigusa, Ikuko N Motoike, Mana Kogure, Naoki Nakaya, Atsushi Hozawa, Shinichi Kuriyama, Masayuki Yamamoto, Seizo Koshiba, Kengo Kinoshita

Metabolomics : Official journal of the Metabolomic Society　20　(2)　34-34　2024年3月5日

DOI： 10.1007/s11306-024-02087-1 　

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INTRODUCTION: Accumulating data on the associations between food consumption and lipid composition in the body is essential for understanding the effects of dietary habits on health. OBJECTIVES: As part of omics research in the Tohoku Medical Megabank Community-Based Cohort Study, this study sought to reveal the dietary impact on plasma lipid concentration in a Japanese population. METHODS: We conducted a correlation analysis of food consumption and plasma lipid concentrations measured using mass spectrometry, for 4032 participants in Miyagi Prefecture, Japan. RESULTS: Our analysis revealed 83 marked correlations between six food categories and the concentrations of plasma lipids in nine subclasses. Previously reported associations, including those between seafood consumption and omega-3 fatty acids, were validated, while those between dairy product consumption and odd-carbon-number fatty acids (odd-FAs) were validated for the first time in an Asian population. Further analysis suggested that dairy product consumption is associated with odd-FAs via sphingomyelin (SM), which suggests that SM is a carrier of odd-FAs. These results are important for understanding odd-FA metabolism with regards to dairy product consumption. CONCLUSION: This study provides insight into the dietary impact on plasma lipid concentration in a Japanese population.
Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS) 査読有り

Sei Harada, Miho Iida, Naoko Miyagawa, Aya Hirata, Kazuyo Kuwabara, Minako Matsumoto, Tomonori Okamura, Shun Edagawa, Yoko Kawada, Atsuko Miyake, Ryota Toki, Miki Akiyama, Atsuki Kawai, Daisuke Sugiyama, Yasunori Sato, Ryo Takemura, Kota Fukai, Yoshiki Ishibashi, Suzuka Kato, Ayako Kurihara, Mizuki Sata, Takuma Shibuki, Ayano Takeuchi, Shun Kohsaka, Mitsuaki Sawano, Satoshi Shoji, Yoshikane Izawa, Masahiro Katsumata, Koichi Oki, Shinichi Takahashi, Tsubasa Takizawa, Hiroshi Maruya, Yuji Nishiwaki, Ryo Kawasaki, Akiyoshi Hirayama, Takamasa Ishikawa, Rintaro Saito, Asako Sato, Tomoyoshi Soga, Masahiro Sugimoto, Masaru Tomita, Shohei Komaki, Hideki Ohmomo, Kanako Ono, Yayoi Otsuka-Yamasaki, Atsushi Shimizu, Yoichi Sutoh, Atsushi Hozawa, Kengo Kinoshita, Seizo Koshiba, Kazuki Kumada

Journal of Epidemiology　2024年1月

DOI： 10.2188/jea.je20230192 　

ISSN：0917-5040 1349-9092
Effect of Nicotinamide Mononucleotide Concentration in Human Milk on Neurodevelopmental Outcome: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. 国際誌

Yoshie Saito, Keigo Sato, Shinji Jinno, Yoshitaka Nakamura, Takahiro Nobukuni, Soichi Ogishima, Satoshi Mizuno, Seizo Koshiba, Shinichi Kuriyama, Kinuko Ohneda, Masashi Morifuji

Nutrients　16　(1)　2023年12月31日

DOI： 10.3390/nu16010145 　

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(1) Background: Breast milk is the only source of nutrition for breastfed infants, but few studies have examined the relationship between breast milk micronutrients and infant neurodevelopmental outcome in exclusively breastfed infants. The aim of this study was to characterize the association between nicotinamide adenine dinucleotide (NAD)-related compounds in the breast milk of Japanese subjects and infant neurodevelopmental outcome. (2) Methods: A total of 150 mother-child pairs were randomly selected from the three-generation cohort of the Tohoku Medical Megabank in Japan. Infants were exclusively breastfed for up to 6 months. Breast milk was collected at 1 month postpartum, and the quantity of NAD-related substances in the breast milk was quantified. The mothers also completed developmental questionnaires at 6, 12, and 24 months. The relationship between the concentration of NAD-related substances in breast milk and developmental indicators was evaluated via ordinal logistic regression analysis. (3) Results: Nicotinamide mononucleotide (NMN) was quantified as the major NAD precursor in breast milk. The median amount of NMN in the breast milk was 9.2 μM. The NMN concentration in breast milk was the only NAD-related substance in breast milk that showed a significant positive correlation with neurodevelopmental outcome in infants at 24 months. (4) Conclusions: The results suggest that NMN in human milk may be an important nutrient for early childhood development.
jMorp: Japanese Multi-Omics Reference Panel update report 2023. 国際誌査読有り

Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　2023年11月1日

DOI： 10.1093/nar/gkad978 　

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Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.
Identification of predictive biomarkers for endometrial cancer diagnosis and treatment response monitoring using plasma metabolome profiling

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Yoshiko Shima, Bin Li, Ikuko N. Motoike, Yusuke Shibuya, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi

Cancer & Metabolism　11　(1)　2023年10月11日
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1186/s40170-023-00317-z 　

eISSN：2049-3002

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Abstract Background Endometrial cancer (EMC) is the most common female genital tract malignancy with an increasing prevalence in many countries including Japan, a fact that renders early detection and treatment necessary to protect health and fertility. Although early detection and treatment are necessary to further improve the prognosis of women with endometrial cancer, biomarkers that accurately reflect the pathophysiology of EMC patients are still unclear. Therefore, it is clinically critical to identify biomarkers to assess diagnosis and treatment efficacy to facilitate appropriate treatment and development of new therapies for EMC. Methods In this study, wide-targeted plasma metabolome analysis was performed to identify biomarkers for EMC diagnosis and the prediction of treatment responses. The absolute quantification of 628 metabolites in plasma samples from 142 patients with EMC was performed using ultra-high-performance liquid chromatography with tandem mass spectrometry. Results The concentrations of 111 metabolites increased significantly, while the concentrations of 148 metabolites decreased significantly in patients with EMC compared to healthy controls. Specifically, LysoPC and TGs, including unsaturated fatty acids, were reduced in patients with stage IA EMC compared to healthy controls, indicating that these metabolic profiles could be used as early diagnostic markers of EMC. In contrast, blood levels of amino acids such as histidine and tryptophan decreased as the risk of recurrence increased and the stages of EMC advanced. Furthermore, a marked increase in total TG and a decrease in specific TGs and free fatty acids including polyunsaturated fatty acids levels were observed in patients with EMC. These results suggest that the polyunsaturated fatty acids in patients with EMC are crucial for disease progression. Conclusions Our data identified specific metabolite profiles that reflect the pathogenesis of EMC and showed that these metabolites correlate with the risk of recurrence and disease stage. Analysis of changes in plasma metabolite profiles could be applied for the early diagnosis and monitoring of the course of treatment of EMC patients.
Association Between Olfactory Test Data with Multiple Levels of Odor Intensity and Suspected Cognitive Impairment: A Cross-Sectional Study. 国際誌

Shuichi Sato, Takao Imaeda, Shunji Mugikura, Naoko Mori, Masaki Takanashi, Kazumi Hayakawa, Tomo Saito, Makiko Taira, Akira Narita, Mana Kogure, Ippei Chiba, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Ryosuke Ishiwata, Tomohiro Nakamura, Ikuko N Motoike, Naoki Nakaya, Seizo Koshiba, Kengo Kinoshita, Shinichi Kuriyama, Soichi Ogishima, Fuji Nagami, Nobuo Fuse, Atsushi Hozawa

Journal of Alzheimer's disease : JAD　2023年9月11日

DOI： 10.3233/JAD-230318 　

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BACKGROUND: Olfactory function decline has recently been reported to be associated with a risk of cognitive impairment. Few population-based studies have included younger adults when examining the association between olfactory test data with multiple odor intensities and suspected cognitive impairment. OBJECTIVE: We investigated the association between high-resolution olfactory test data with fewer odors and suspected cognitive impairments. We also examined the differences between older and younger adults in this association. METHODS: The Japanese version of the Montreal Cognitive Assessment (MoCA-J) was administered to 1,450 participants, with three odor-intensity-level olfactometry using six different odors. Logistic regressions to discriminate suspected cognitive impairment were conducted to examine the association, adjusted for age, sex, education duration, and smoking history. Data were collected from the Program by Tohoku University Tohoku Medical Megabank Organization, with an additional olfactory test conducted between 2019 and 2021. RESULTS: We generally observed that the lower the limit of distinguishable odor intensity was, the higher the MoCA-J score was. The combination of spearmint and stuffy socks contributed most to the distinction between suspected and unsuspected cognitive impairment. Furthermore, the association was significant in women aged 60-74 years (adjusted odds ratio 0.881, 95% confidence interval [0.790, 0.983], p = 0.024). CONCLUSIONS: The results indicate an association between the limit of distinguishable odor intensity and cognitive function. The olfactory test with multiple odor intensity levels using fewer odors may be applicable for the early detection of mild cognitive impairment, especially in older women aged 60-74 years.
Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes. 国際誌

Marta Anna Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano

Hepatology (Baltimore, Md.)　2023年8月21日

DOI： 10.1097/HEP.0000000000000568 　

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BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear. APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3. CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.
Identification of predictive biomarkers for diagnosis and radiation sensitivity of uterine cervical cancer using wide-targeted metabolomics. 国際誌

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Bin Li, Ikuko N Motoike, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi

The journal of obstetrics and gynaecology research　49　(8)　2109-2117　2023年6月9日

DOI： 10.1111/jog.15709 　

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AIM: Uterine cervical cancer (UCC) is the fourth most common cancer in women, responsible for more than 300 000 deaths worldwide. Its early detection, by cervical cytology, and prevention, by vaccinating against human papilloma virus, greatly contribute to reducing cervical cancer mortality in women. However, penetration of the effective prevention of UCC in Japan remains low. Plasma metabolome analysis is widely used for biomarker discovery and the identification of cancer-specific metabolic pathways. Here, we aimed to identify predictive biomarkers for the diagnosis and radiation sensitivity of UCC using wide-targeted plasma metabolomics. METHODS: We analyzed 628 metabolites in plasma samples obtained from 45 patients with UCC using ultra-high-performance liquid chromatography with tandem mass spectrometry. RESULTS: The levels of 47 metabolites were significantly increased and those of 75 metabolites were significantly decreased in patients with UCC relative to healthy controls. Increased levels of arginine and ceramides, and decreased levels of tryptophan, ornithine, glycosylceramides, lysophosphatidylcholine, and phosphatidylcholine were characteristic of patients with UCC. Comparison of metabolite profiles in groups susceptible and non-susceptible to radiation therapy, a treatment for UCC, revealed marked variations in polyunsaturated fatty acid, nucleic acid, and arginine metabolism in the group not susceptible to treatment. CONCLUSIONS: Our findings suggest that the metabolite profile of patients with UCC may be an important indicator for distinguishing these patients from healthy cohorts, and may also be useful for predicting sensitivity to radiotherapy.
Identification of predictive biomarkers for diagnosis and radiation sensitivity of uterine cervical cancer using wide‐targeted metabolomics

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Bin Li, Ikuko N. Motoike, Tatsuya Hagihara, Shogo Shigeta, Hideki Tokunaga, Daisuke Saigusa, Kengo Kinoshita, Seizo Koshiba, Nobuo Yaegashi

Journal of Obstetrics and Gynaecology Research　2023年6月9日
出版者・発行元： Wiley
DOI： 10.1111/jog.15709 　

ISSN：1341-8076

eISSN：1447-0756
日本人集団における食習慣と血漿中脂質濃度の関連解析

佐藤允治, 菱沼英史, 三枝大輔, 元池育子, 木下賢吾, 小柴生造

脂質生化学研究　65　291-292　2023年5月
出版者・発行元：日本脂質生化学会
ISSN：0285-1520
Decreased β‐hydroxybutyrate and ketogenic amino acid levels in depressed human adults

Shiho Sato, Zhiqian Yu, Mai Sakai, Ikuko N. Motoike, Daisuke Saigusa, Ryo Hirayama, Yoshie Kikuchi, Takaaki Abe, Kengo Kinoshita, Seizo Koshiba, Hiroaki Tomita

European Journal of Neuroscience　2023年2月7日
出版者・発行元： Wiley
DOI： 10.1111/ejn.15931 　

ISSN：0953-816X

eISSN：1460-9568
血清メタボロームと認知機能変化の関連 NILS-LSAの観察結果から

寳澤篤, 大塚礼, 張シュ, 菱沼英史, 元池育子, 三枝大輔, 中谷直樹, 小柴生造, 荒井秀典

Journal of Epidemiology　33　(Suppl.1)　87-87　2023年2月
出版者・発行元： (一社)日本疫学会
ISSN：0917-5040

eISSN：1349-9092
Plasma metabolic disturbances during pregnancy and postpartum in women with depression. 国際誌査読有り

Zhiqian Yu, Naomi Matsukawa, Daisuke Saigusa, Ikuko N Motoike, Chiaki Ono, Yasunobu Okamura, Tomomi Onuma, Yuta Takahashi, Mai Sakai, Hisaaki Kudo, Taku Obara, Keiko Murakami, Matusyuki Shirota, Saya Kikuchi, Natsuko Kobayashi, Yoshie Kikuchi, Junichi Sugawara, Naoko Minegishi, Soichi Ogishima, Kengo Kinoshita, Masayuki Yamamoto, Nobuo Yaegashi, Shinichi Kuriyama, Seizo Koshiba, Hiroaki Tomita

iScience　25　(12)　105666-105666　2022年12月22日

DOI： 10.1016/j.isci.2022.105666 　

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Examining plasma metabolic profiling during pregnancy and postpartum could help clinicians understand the risk factors for postpartum depression (PPD) development. This analysis targeted paired plasma metabolites in mid-late gestational and 1 month postpartum periods in women with (n = 209) or without (n = 222) PPD. Gas chromatogram-mass spectrometry was used to analyze plasma metabolites at these two time points. Among the 170 objected plasma metabolites, principal component analysis distinguished pregnancy and postpartum metabolites but failed to discriminate women with and without PPD. Compared to women without PPD, those with PPD exhibited 37 metabolites with disparate changes during pregnancy and the 1-month postpartum period and an enriched citrate cycle. Machine learning and multivariate statistical analysis identified two or three compounds that could be potential biomarkers for PPD prediction during pregnancy. Our findings suggest metabolic disturbances in women with depression and may help to elucidate metabolic processes associated with PPD development.
Genome-wide association study of the risk of chronic kidney disease and kidney-related traits in the Japanese population: J-Kidney-Biobank. 国際誌査読有り

Yuka Sugawara, Yosuke Hirakawa, Hajime Nagasu, Akira Narita, Akihiro Katayama, Jun Wada, Miho Shimizu, Takashi Wada, Hiromasa Kitamura, Toshiaki Nakano, Hideki Yokoi, Motoko Yanagita, Shin Goto, Ichiei Narita, Seizo Koshiba, Gen Tamiya, Masaomi Nangaku, Masayuki Yamamoto, Naoki Kashihara

Journal of human genetics　68　(2)　55-64　2022年11月21日

DOI： 10.1038/s10038-022-01094-1 　

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Chronic kidney disease (CKD) is a syndrome characterized by a gradual loss of kidney function with decreased estimated glomerular filtration rate (eGFR), which may be accompanied by an increase in the urine albumin-to-creatinine ratio (UACR). Although trans-ethnic genome-wide association studies (GWASs) have been conducted for kidney-related traits, there have been few analyses in the Japanese population, especially for the UACR trait. In this study, we conducted a GWAS to identify loci related to multiple kidney-related traits in Japanese individuals. First, to detect loci associated with CKD, eGFR, and UACR, we performed separate GWASs with the following two datasets: 475 cases of CKD diagnosed at seven university hospitals and 3471 healthy subjects (dataset 1) and 3664 cases of CKD-suspected individuals with eGFR <60 ml/min/1.73 m2 or urinary protein ≥ 1+ and 5952 healthy subjects (dataset 2). Second, we performed a meta-analysis between these two datasets and detected the following associated loci: 10 loci for CKD, 9 loci for eGFR, and 22 loci for UACR. Among the loci detected, 22 have never been reported previously. Half of the significant loci for CKD were shared with those for eGFR, whereas most of the loci associated with UACR were different from those associated with CKD or eGFR. The GWAS of the Japanese population identified novel genetic components that were not previously detected. The results also suggest that the group primarily characterized by increased UACR possessed genetically different features from the group characterized by decreased eGFR.
遺伝・生活習慣が日本人の血中代謝プロファイルに与える影響の解析

小柴生造, 元池育子, 井上仁, 菱沼英史, 青木裕一, 櫻井美由紀, 佐藤允治, 七谷圭, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　95回　1T17e-02　2022年11月
出版者・発行元： (公社)日本生化学会
jMorp: Japanese Multi Omics Reference Panel

田高周, 菱沼英史, 井上仁, 青木裕一, 岡村容伸, 川嶋順子, 大槻晃史, 田口恵子, 菅野貴成, 元池育子, 勝岡史城, 小柴生造, 木下賢吾

トーゴーの日2022　1　2022年10月5日
出版者・発行元： JST NBDC事業推進部
DOI： 10.18908/togo2022.p040 　
メタボローム解析による糖尿病網膜症のバイオマーカーの探索

安田正幸, 國方彦志, 児玉慎二郎, 岡部達, 菱沼英史, 瀧澤廣輝, 片桐秀樹, 小柴生造, 中澤徹

日本眼科学会雑誌　126　(臨増)　168-168　2022年3月
出版者・発行元： (公財)日本眼科学会
ISSN：0029-0203
Esterification promotes the intracellular accumulation of roxadustat, an activator of hypoxia-inducible factors, to extend its effective duration. 国際誌

Taku Nakai, Daisuke Saigusa, Yuma Iwamura, Yotaro Matsumoto, Keiko Umeda, Koichiro Kato, Hayato Yamaki, Yoshihisa Tomioka, Ikuo Hirano, Seizo Koshiba, Masayuki Yamamoto, Norio Suzuki

Biochemical pharmacology　197　114939-114939　2022年3月

DOI： 10.1016/j.bcp.2022.114939 　

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Kidney injury often causes anemia due to a lack of production of the erythroid growth factor erythropoietin (EPO) in the kidneys. Roxadustat is one of the first oral medicines inducing EPO production in patients with renal anemia by activating hypoxia-inducible factors (HIFs), which are activators of EPO gene expression. In this study, to develop prodrugs of roxadustat with improved permeability through cell membrane, we investigated the effects of 8 types of esterification on the pharmacokinetics and bioactivity of roxadustat using Hep3B hepatoma cells that HIF-dependently produce EPO. Mass spectrometry of cells incubated with the esterified roxadustat derivatives revealed that the designed compounds were deesterified after being taken up by cells and showed low cytotoxicity compared to the original compound. Esterification prolonged the effective duration of roxadustat with respect to EPO gene induction and HIF activation in cells transiently exposed to the compounds. In the kidneys and livers of mice, both of which are unique sites of EPO production, a majority of the methyl-esterified roxadustat was deesterified within 6 h after drug administration. The deesterified roxadustat derivative was continuously detectable in plasma and urine for at least 48 h after administration, while the administered compound became undetectable 24 h after administration. Additionally, we confirmed that methyl-esterified roxadustat activated erythropoiesis in mice by inducing Epo mRNA expression exclusively in renal interstitial cells, which have intrinsic EPO-producing potential. These data suggest that esterification could lead to the development of roxadustat prodrugs with improvements in cell membrane permeability, effective duration and cytotoxicity.
dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project. 国際誌

Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Akito Tsuboi, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Mika Sakurai, Satoshi Makino, Gen Tamiya, Yuichi Aoki, Ritsuko Shimizu, Ikuko N Motoike, Seizo Koshiba, Naoko Minegishi, Kazuki Kumada, Takahiro Nobukuni, Kichiya Suzuki, Inaho Danjoh, Fuji Nagami, Kozo Tanno, Hideki Ohmomo, Koichi Asahi, Atsushi Shimizu, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Teiji Tominaga, Shigeo Kure, Nobuo Yaegashi, Kengo Kinoshita, Makoto Sasaki, Hiroshi Tanaka, Masayuki Yamamoto

Human genome variation　8　(1)　44-44　2021年12月10日

DOI： 10.1038/s41439-021-00175-5 　

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To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.
Nrf2 plays a critical role in the metabolic response during and after spaceflight. 国際誌

Akira Uruno, Daisuke Saigusa, Takafumi Suzuki, Akane Yumoto, Tomohiro Nakamura, Naomi Matsukawa, Takahiro Yamazaki, Ristumi Saito, Keiko Taguchi, Mikiko Suzuki, Norio Suzuki, Akihito Otsuki, Fumiki Katsuoka, Eiji Hishinuma, Risa Okada, Seizo Koshiba, Yoshihisa Tomioka, Ritsuko Shimizu, Masaki Shirakawa, Thomas W Kensler, Dai Shiba, Masayuki Yamamoto

Communications biology　4　(1)　1381-1381　2021年12月9日

DOI： 10.1038/s42003-021-02904-6 　

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Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.
代謝プロファイルに影響を与える遺伝要因の網羅的解析

小柴生造, 元池育子, 三枝大輔, 井上仁, 菱沼英史, 青木裕一, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　94回　[P-837]　2021年11月
出版者・発行元： (公社)日本生化学会
Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs. 国際誌

Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

Journal of biochemistry　170　(3)　399-410　2021年10月12日

DOI： 10.1093/jb/mvab060 　

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Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin >2.5-5% were >0.9 and >0.8, respectively, and >12 million markers were imputed with an INFO score >0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.
A cross-population atlas of genetic associations for 220 human phenotypes. 国際誌

Saori Sakaue, Masahiro Kanai, Yosuke Tanigawa, Juha Karjalainen, Mitja Kurki, Seizo Koshiba, Akira Narita, Takahiro Konuma, Kenichi Yamamoto, Masato Akiyama, Kazuyoshi Ishigaki, Akari Suzuki, Ken Suzuki, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Shinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yukihiro Koretsune, Kaoru Ito, Chikashi Terao, Toshimasa Yamauchi, Issei Komuro, Takashi Kadowaki, Gen Tamiya, Masayuki Yamamoto, Yusuke Nakamura, Michiaki Kubo, Yoshinori Murakami, Kazuhiko Yamamoto, Yoichiro Kamatani, Aarno Palotie, Manuel A Rivas, Mark J Daly, Koichi Matsuda, Yukinori Okada

Nature genetics　53　(10)　1415-1424　2021年10月

DOI： 10.1038/s41588-021-00931-x 　

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Current genome-wide association studies do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype genome-wide association studies (diseases, biomarkers and medication usage) in BioBank Japan (n = 179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (ntotal = 628,000) identified ~5,000 new loci, which improved the resolution of the genomic map of human traits. This atlas elucidated the landscape of pleiotropy as represented by the major histocompatibility complex locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically informed subtyping of similar diseases (for example, allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.
Comparison of Kit-Based Metabolomics with Other Methodologies in a Large Cohort, towards Establishing Reference Values

Daisuke Saigusa, Eiji Hishinuma, Naomi Matsukawa, Masatomo Takahashi, Jin Inoue, Shu Tadaka, Ikuko N. Motoike, Atsushi Hozawa, Yoshihiro Izumi, Takeshi Bamba, Kengo Kinoshita, Kim Ekroos, Seizo Koshiba, Masayuki Yamamoto

Metabolites　11　(10)　652-652　2021年9月24日
出版者・発行元： MDPI AG
DOI： 10.3390/metabo11100652 　

eISSN：2218-1989

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Metabolic profiling is an omics approach that can be used to observe phenotypic changes, making it particularly attractive for biomarker discovery. Although several candidate metabolites biomarkers for disease expression have been identified in recent clinical studies, the reference values of healthy subjects have not been established. In particular, the accuracy of concentrations measured by mass spectrometry (MS) is unclear. Therefore, comprehensive metabolic profiling in large-scale cohorts by MS to create a database with reference ranges is essential for evaluating the quality of the discovered biomarkers. In this study, we tested 8700 plasma samples by commercial kit-based metabolomics and separated them into two groups of 6159 and 2541 analyses based on the different ultra-high-performance tandem mass spectrometry (UHPLC-MS/MS) systems. We evaluated the quality of the quantified values of the detected metabolites from the reference materials in the group of 2541 compared with the quantified values from other platforms, such as nuclear magnetic resonance (NMR), supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS) and UHPLC-Fourier transform mass spectrometry (FTMS). The values of the amino acids were highly correlated with the NMR results, and lipid species such as phosphatidylcholines and ceramides showed good correlation, while the values of triglycerides and cholesterol esters correlated less to the lipidomics analyses performed using SFC-MS/MS and UHPLC-FTMS. The evaluation of the quantified values by MS-based techniques is essential for metabolic profiling in a large-scale cohort.
Machine learning approaches to predict gestational age in normal and complicated pregnancies via urinary metabolomics analysis. 国際誌

Takafumi Yamauchi, Daisuke Ochi, Naomi Matsukawa, Daisuke Saigusa, Mami Ishikuro, Taku Obara, Yoshiki Tsunemoto, Satsuki Kumatani, Riu Yamashita, Osamu Tanabe, Naoko Minegishi, Seizo Koshiba, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Masao Nagasaki, Satoshi Hiyama, Junichi Sugawara

Scientific reports　11　(1)　17777-17777　2021年9月7日

DOI： 10.1038/s41598-021-97342-z 　

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The elucidation of dynamic metabolomic changes during gestation is particularly important for the development of methods to evaluate pregnancy status or achieve earlier detection of pregnancy-related complications. Some studies have constructed models to evaluate pregnancy status and predict gestational age using omics data from blood biospecimens; however, less invasive methods are desired. Here we propose a model to predict gestational age, using urinary metabolite information. In our prospective cohort study, we collected 2741 urine samples from 187 healthy pregnant women, 23 patients with hypertensive disorders of pregnancy, and 14 patients with spontaneous preterm birth. Using gas chromatography-tandem mass spectrometry, we identified 184 urinary metabolites that showed dynamic systematic changes in healthy pregnant women according to gestational age. A model to predict gestational age during normal pregnancy progression was constructed; the correlation coefficient between actual and predicted weeks of gestation was 0.86. The predicted gestational ages of cases with hypertensive disorders of pregnancy exhibited significant progression, compared with actual gestational ages. This is the first study to predict gestational age in normal and complicated pregnancies by using urinary metabolite information. Minimally invasive urinary metabolomics might facilitate changes in the prediction of gestational age in various clinical settings.
Wide-Targeted Metabolome Analysis Identifies Potential Biomarkers for Prognosis Prediction of Epithelial Ovarian Cancer. 国際誌

Eiji Hishinuma, Muneaki Shimada, Naomi Matsukawa, Daisuke Saigusa, Bin Li, Kei Kudo, Keita Tsuji, Shogo Shigeta, Hideki Tokunaga, Kazuki Kumada, Keigo Komine, Hidekazu Shirota, Yuichi Aoki, Ikuko N Motoike, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto, Seizo Koshiba, Nobuo Yaegashi

Toxins　13　(7)　2021年6月30日

DOI： 10.3390/toxins13070461 　

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Epithelial ovarian cancer (EOC) is a fatal gynecologic cancer, and its poor prognosis is mainly due to delayed diagnosis. Therefore, biomarker identification and prognosis prediction are crucial in EOC. Altered cell metabolism is a characteristic feature of cancers, and metabolomics reflects an individual's current phenotype. In particular, plasma metabolome analyses can be useful for biomarker identification. In this study, we analyzed 624 metabolites, including uremic toxins (UTx) in plasma derived from 80 patients with EOC using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Compared with the healthy control, we detected 77 significantly increased metabolites and 114 significantly decreased metabolites in EOC patients. Especially, decreased concentrations of lysophosphatidylcholines and phosphatidylcholines and increased concentrations of triglycerides were observed, indicating a metabolic profile characteristic of EOC patients. After calculating the parameters of each metabolic index, we found that higher ratios of kynurenine to tryptophan correlates with worse prognosis in EOC patients. Kynurenine, one of the UTx, can affect the prognosis of EOC. Our results demonstrated that plasma metabolome analysis is useful not only for the diagnosis of EOC, but also for predicting prognosis with the variation of UTx and evaluating response to chemotherapy.
Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism 国際誌査読有り

Yuta Horie, Takafumi Suzuki, Jin Inoue, Tatsuro Iso, Geoffrey Wells, Terry W. Moore, Tsunehiro Mizushima, Albena T. Dinkova-Kostova, Takuma Kasai, Takashi Kamei, Seizo Koshiba, Masayuki Yamamoto

Communications Biology　4　(1)　576-576　2021年5月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s42003-021-02100-6 　

eISSN：2399-3642

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<title>Abstract</title>The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers_. This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI.
Identification of biomarkers to diagnose diseases and find adverse drug reactions by metabolomics. 国際誌

Daisuke Saigusa, Naomi Matsukawa, Eiji Hishinuma, Seizo Koshiba

Drug metabolism and pharmacokinetics　37　100373-100373　2021年4月

DOI： 10.1016/j.dmpk.2020.11.008 　

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Metabolomics has been widely used for investigating the biological functions of disease expression and has the potential to discover biomarkers in circulating biofluids or tissue extracts that reflect in phenotypic changes. Metabolic profiling has advantages because of the use of unbiased techniques, including multivariate analysis, and has been applied in pharmacological studies to predict therapeutic and adverse reactions of drugs, which is called pharmacometabolomics (PMx). Nuclear magnetic resonance (NMR)- and mass spectrometry (MS)-based metabolomics has contributed to the discovery of recent disease biomarkers; however, the optimal strategy for the study purpose must be selected from many established protocols, methodologies and analytical platforms. Additionally, information on molecular localization in tissue is essential for further functional analyses related to therapeutic and adverse effects of drugs in the process of drug development. MS imaging (MSI) is a promising technology that can visualize molecules on tissue surfaces without labeling and thus provide localized information. This review summarizes recent uses of MS-based global and wide-targeted metabolomics technologies and the advantages of the MSI approach for PMx and highlights the PMx technique for the biomarker discovery of adverse drug effects.
新規に同定したガラクトース血症IV型における国内頻度と臨床像に関する研究

和田陽一, 菊池敦生, 岩澤伸哉, 市野井那津子, 小柴生造, 呉繁夫

日本小児科学会雑誌　125　(2)　203-203　2021年2月
出版者・発行元： (公社)日本小児科学会
ISSN：0001-6543
jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. 国際誌

Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　49　(D1)　D536-D544　2021年1月8日

DOI： 10.1093/nar/gkaa1034 　

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In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.
Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia.

Yasuo Uchida, Tomoya Higuchi, Matsuyuki Shirota, Satoshi Kagami, Daisuke Saigusa, Seizo Koshiba, Jun Yasuda, Gen Tamiya, Shinichi Kuriyama, Kengo Kinoshita, Nobuo Yaegashi, Masayuki Yamamoto, Tetsuya Terasaki, Junichi Sugawara

Biological & pharmaceutical bulletin　44　(6)　804-815　2021年

DOI： 10.1248/bpb.b20-01043 　

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The purpose of the present study was to identify a plasma protein biomarker able to predict pre-eclampsia (PE). Comprehensive quantitative proteomics using mass spectrometry with sequential window acquisition of all theoretical fragment ion spectra (SWATH-MS) was applied to plasma samples of 7 PE and 14 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE), and 11 proteins were selected as candidates potentially able to differentiate the two groups. Plasmas collected at gestational weeks 14-24 from 36 PE and 120 healthy pregnant women (for PE subjects, plasma samples were taken before onset of PE) were used to conduct selected reaction monitoring quantification analysis, optimize protein combinations and conduct internal validation, which consisted of 30 iterations of 10-fold cross-validation using multivariate logistic regression and receiver operating characteristic (ROC) analysis. The combination of afamin, fibronectin, and sex-hormone-binding globulin was selected as the best candidate. The 3-protein combination predictive model (predictive equation and cut-off value) generated using the internal validation subjects was successfully validated in another group of validation subjects (36 PE and 54 healthy (for PE subjects, plasma samples were taken before onset of PE)) and showed good predictive performance, with the area under the curve (AUC) 0.835 and odds ratio 13.43. In conclusion, we newly identified a 3-protein combination biomarker and established a predictive equation and cut-off value that can predict the onset of PE based on analysis of plasma samples collected during gestational weeks 14-24.
Improved metabolomic data-based prediction of depressive symptoms using nonlinear machine learning with feature selection 査読有り

Yuta Takahashi, Masao Ueki, Makoto Yamada, Gen Tamiya, Ikuko N. Motoike, Daisuke Saigusa, Miyuki Sakurai, Fuji Nagami, Soichi Ogishima, Seizo Koshiba, Kengo Kinoshita, Masayuki Yamamoto, Hiroaki Tomita

Translational Psychiatry　10　(1)　2020年12月1日

DOI： 10.1038/s41398-020-0831-9 　

eISSN：2158-3188
A global atlas of genetic associations of 220 deep phenotypes

Saori Sakaue, Masahiro Kanai, Yosuke Tanigawa, Juha Karjalainen, Mitja Kurki, Seizo Koshiba, Akira Narita, Takahiro Konuma, Kenichi Yamamoto, Masato Akiyama, Kazuyoshi Ishigaki, Akari Suzuki, Ken Suzuki, Wataru Obara, Ken Yamaji, Kazuhisa Takahashi, Satoshi Asai, Yasuo Takahashi, Takao Suzuki, Nobuaki Shinozaki, Hiroki Yamaguchi, Shiro Minami, Shigeo Murayama, Kozo Yoshimori, Satoshi Nagayama, Daisuke Obata, Masahiko Higashiyama, Akihide Masumoto, Yukihiro Koretsune, Kaoru Ito FinnGen, Chikashi Terao, Toshimasa Yamauchi, Issei Komuro, Takashi Kadowaki, Gen Tamiya, Masayuki Yamamoto, Yusuke Nakamura, Michiaki Kubo, Yoshinori Murakami, Kazuhiko Yamamoto, Yoichiro Kamatani, Aarno Palotie, Manuel A. Rivas, Mark J. Daly, Koichi Matsuda, Yukinori Okada

2020年10月27日
出版者・発行元： Cold Spring Harbor Laboratory
DOI： 10.1101/2020.10.23.20213652 　

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<title>Abstract</title>Current genome-wide association studies (GWASs) do not yet capture sufficient diversity in populations and scope of phenotypes. To expand an atlas of genetic associations in non-European populations, we conducted 220 deep-phenotype GWASs (diseases, biomarkers, and medication usage) in BioBank Japan (<italic>n</italic>=179,000), by incorporating past medical history and text-mining of electronic medical records. Meta-analyses with the UK Biobank and FinnGen (<italic>n</italic>_total=628,000) identified ∼5,000 novel loci, which improved the resolution of genomic map of human traits. This atlas elucidated landscape of pleiotropy as represented by MHC locus, where we conducted HLA fine-mapping. Finally, we performed statistical decomposition of matrices of phenome-wide summary statistics, and identified latent genetic components, which pinpointed responsible variants and biological mechanisms underlying current disease classifications across populations. The decomposed components enabled genetically-informed subtyping of similar diseases (e.g., allergic diseases). Our study suggests a potential avenue for hypothesis-free re-investigation of human diseases through genetics.
Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

Junichi Sugawara, Mami Ishikuro, Taku Obara, Tomomi Onuma, Keiko Murakami, Masahiro Kikuya, Fumihiko Ueno, Aoi Noda, Satoshi Mizuno, Tomoko Kobayashi, Yohei Hamanaka, Kichiya Suzuki, Eiichi Kodama, Naho Tsuchiya, Akira Uruno, Yoichi Suzuki, Osamu Tanabe, Hideyasu Kiyomoto, Akito Tsuboi, Atsushi Shimizu, Seizo Koshiba, Naoko Minegishi, Soichi Ogishima, Gen Tamiya, Hirohito Metoki, Atsushi Hozawa, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Shinichi Kuriyama, Masayuki Yamamoto

Journal of epidemiology　32　(2)　69-79　2020年10月10日

DOI： 10.2188/jea.JE20200338 　

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BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.
Erratum: Author Correction: Nrf2 contributes to the weight gain of mice during space travel (Communications biology (2020) 3 1 (496)) 査読有り

Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W. Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

Communications biology　3　(1)　566　2020年10月7日

DOI： 10.1038/s42003-020-01292-7 　

eISSN：2399-3642
Identification of critical genetic variants associated with metabolic phenotypes of the Japanese population 国際誌査読有り

Seizo Koshiba, Ikuko N. Motoike, Daisuke Saigusa, Jin Inoue, Yuichi Aoki, Shu Tadaka, Matsuyuki Shirota, Fumiki Katsuoka, Gen Tamiya, Naoko Minegishi, Nobuo Fuse, Kengo Kinoshita, Masayuki Yamamoto

Communications Biology　3　(1)　662-662　2020年10月
出版者・発行元： Springer Science and Business Media LLC
DOI： 10.1038/s42003-020-01383-5 　

eISSN：2399-3642

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<title>Abstract</title> We performed a metabolome genome-wide association study for the Japanese population in the prospective cohort study of Tohoku Medical Megabank. By combining whole-genome sequencing and nontarget metabolome analyses, we identified a large number of novel associations between genetic variants and plasma metabolites. Of the identified metabolite-associated genes, approximately half have already been shown to be involved in various diseases. We identified metabolite-associated genes involved in the metabolism of xenobiotics, some of which are from intestinal microorganisms, indicating that the identified genetic variants also markedly influence the interaction between the host and symbiotic bacteria. We also identified five associations that appeared to be female-specific. A number of rare variants that influence metabolite levels were also found, and combinations of common and rare variants influenced the metabolite levels more profoundly. These results support our contention that metabolic phenotyping provides important insights into how genetic and environmental factors provoke human diseases.
Nrf2 contributes to the weight gain of mice during space travel. 国際誌

Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

Communications biology　3　(1)　496-496　2020年9月8日

DOI： 10.1038/s42003-020-01227-2 　

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Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.
O-Glycan-Altered Extracellular Vesicles: A Specific Serum Marker Elevated in Pancreatic Cancer. 国際誌

Takahiro Yokose, Yasuaki Kabe, Atsushi Matsuda, Minoru Kitago, Sachiko Matsuda, Miwa Hirai, Tomomi Nakagawa, Yohei Masugi, Takako Hishiki, Yuki Nakamura, Masahiro Shinoda, Hiroshi Yagi, Yuta Abe, Go Oshima, Shutaro Hori, Yutaka Nakano, Kazufumi Honda, Ayumi Kashiro, Chigusa Morizane, Satoshi Nara, Shojiro Kikuchi, Takahiko Shibahara, Makoto Itonaga, Masayuki Ono, Naoko Minegishi, Seizo Koshiba, Masayuki Yamamoto, Atsushi Kuno, Hiroshi Handa, Michiie Sakamoto, Makoto Suematsu, Yuko Kitagawa

Cancers　12　(9)　2020年8月31日

DOI： 10.3390/cancers12092469 　

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Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum (two cohorts including 117 PC patients and 98 normal controls) using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA- or ACA-positive EVs were significantly increased in the culture of PC cell lines or in the serum of PC patients including carbohydrate antigen 19-9 negative patients with high area under curve values. The elevated numbers of EVs in PC serum returned to normal levels after pancreatectomy. Histological examination confirmed that the tumors stained with ABA/ACA. These specific EVs with O-glycans recognized by ABA/ACA are elevated in PC sera and can act as potential biomarkers in a liquid biopsy for PC patients screening.
Correction: Biallelic GALM pathogenic variants cause a novel type of galactosemia (Genetics in Medicine, (2019), 21, 6, (1286-1294), 10.1038/s41436-018-0340-x)

Yoichi Wada, Atsuo Kikuchi, Natsuko Arai-Ichinoi, Osamu Sakamoto, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure

Genetics in Medicine　22　(7)　1281　2020年7月1日

DOI： 10.1038/s41436-020-0836-z 　

ISSN：1098-3600

eISSN：1530-0366
Design and Progress of Oral Health Examinations in the Tohoku Medical Megabank Project.

Akito Tsuboi, Hiroyuki Matsui, Naru Shiraishi, Takahisa Murakami, Akihito Otsuki, Junko Kawashima, Tomomi Kiyama, Toru Tamahara, Maki Goto, Shihoko Koyama, Junichi Sugawara, Eiichi N Kodama, Hirohito Metoki, Atsushi Hozawa, Shinichi Kuriyama, Hiroaki Tomita, Masahiro Kikuya, Naoko Minegishi, Kichiya Suzuki, Seizo Koshiba, Gen Tamiya, Nobuo Fuse, Yuichi Aoki, Takako Takai-Igarashi, Soichi Ogishima, Tomohiro Nakamura, Mika Sakurai-Yageta, Fuji Nagami, Kengo Kinoshita, Shigeo Kure, Ritsuko Shimizu, Keiichi Sasaki, Masayuki Yamamoto

The Tohoku journal of experimental medicine　251　(2)　97-115　2020年6月

DOI： 10.1620/tjem.251.97 　

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In order to assess the long-term impact of the Great East Japan Earthquake on the oral health of disaster victims and to evaluate gene-environmental interactions in the development of major oral diseases and oral-systemic associations, the oral part of two large-scale genome cohort studies by the Tohoku Medical Megabank Organization (ToMMo), including the Community-based cohort (CommCohort) study and the Birth and Three-Generation cohort (BirThree) study, have been conducted. The study population comprised 32,185 subjects, including 16,886 participants in the CommCohort study and 15,299 participants in the BirThree cohort study, recruited from 2013 to 2017. The oral studies consist of a questionnaire regarding oral hygiene behavior, clinical examinations by dentists, and oral plaque and saliva sampling for microbiome analyses, which were carried out at seven community support centers in Miyagi prefecture. The median age of all participants was 55.0 years, and 66.1% of participants were women. Almost all participants reported that they brushed their teeth more than once a day. The median number of present teeth was 27.0, and the decayed, missing and filled tooth number was 16.0, with a significant difference according to age and sex. The median periodontal pocket and clinical attachment level was 2.48 mm and 4.00 mm, respectively. Periodontal parameters increased significantly according to age, except for the accumulation of dental calculus. The oral part of these extensive cross-sectional studies provides a unique and important platform for future studies on oral health and diseases that elicit through interactions with systemic diseases, lifestyles, life events and genetic backgrounds, and contributes to researches clarifying the long-term effects of disasters on oral health.
Longitudinal plasma amino acid profiling with maternal genomic background throughout human pregnancy 国際誌査読有り

Matsuyuki Shirota, Daisuke Saigusa, Riu Yamashita, Yasutake Kato, Mitsuyo Matsumoto, Junya Yamagishi, Noriko Ishida, Kazuki Kumada, Yuji Oe, Hisaaki Kudo, Junji Yokozawa, Yoko Kuroki, Ikuko Motoike, Fumiki Katsuoka, Masao Nagasaki, Seizo Koshiba, Keiko Nakayama, Osamu Tanabe, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Hirohito Metoki, Shinichi Kuriyama, Nobuo Yaegashi, Masayuki Yamamoto, Junichi Sugawara

Medical Mass Spectrometry　4　(1)　36-49　2020年4月16日

DOI： 10.24508/mms.2020.06.001 　
Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy.

Tomoyuki Akiyama, Daisuke Saigusa, Yuki Hyodo, Keiko Umeda, Reina Saijo, Seizo Koshiba, Katsuhiro Kobayashi

Acta medica Okayama　74　(1)　65-72　2020年2月

DOI： 10.18926/AMO/57955 　

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To characterize metabolic profiles within the central nervous system in epilepsy, we performed gas chromatography-tandem mass spectrometry (GC-MS/MS)-based metabolome analysis of the cerebrospinal fluid (CSF) in pediatric patients with and without epilepsy. The CSF samples obtained from 64 patients were analyzed by GC-MS/MS. Multivariate analyses were performed for two age groups, 0-5 years of age and 6-17 years of age, to elucidate the effects of epilepsy and antiepileptic drugs on the metabolites. In patients aged 0-5 years (22 patients with epilepsy, 13 without epilepsy), epilepsy patients had reduced 2-ketoglutaric acid and elevated pyridoxamine and tyrosine. In patients aged 6-17 years (12 with epilepsy, 17 without epilepsy), epilepsy patients had reduced 1,5-anhydroglucitol. Valproic acid was associated with elevated 2-aminobutyric acid, 2-ketoisocaproic acid, 4-hydroxyproline, acetylglycine, methionine, N-acetylserine, and serine. Reduced energy metabolism and alteration of vitamin B6 metabolism may play a role in epilepsy in young children. The roles of 1,5-anhydroglucitol in epilepsy in older children and in levetiracetam and zonisamide treatment remain to be explained. Valproic acid influenced the levels of amino acids and related metabolites involved in the metabolism of serine, methionine, and leucine.
Amino-acid selective isotope labeling enables simultaneous overlapping signal decomposition and information extraction from NMR spectra 査読有り

Takuma Kasai, Shunsuke Ono, Seizo Koshiba, Masayuki Yamamoto, Toshiyuki Tanaka, Shiro Ikeda, Takanori Kigawa

Journal of Biomolecular NMR　2020年1月30日

DOI： 10.1007/s10858-019-00295-9 　
Study profile of The Tohoku Medical Megabank Community-Based Cohort Study. 査読有り

Hozawa A, Tanno K, Nakaya N, Nakamura T, Tsuchiya N, Hirata T, Narita A, Kogure M, Nochioka K, Sasaki R, Takanashi N, Otsuka K, Sakata K, Kuriyama S, Kikuya M, Tanabe O, Sugawara J, Suzuki K, Suzuki Y, Kodama EN, Fuse N, Kiyomoto H, Tomita H, Uruno A, Hamanaka Y, Metoki H, Ishikuro M, Obara T, Kobayashi T, Kitatani K, Takai-Igarashi T, Ogishima S, Satoh M, Ohmomo H, Tsuboi A, Egawa S, Ishii T, Ito K, Ito S, Taki Y, Minegishi N, Ishii N, Nagasaki M, Igarashi K, Koshiba S, Shimizu R, Tamiya G, Nakayama K, Motohashi H, Yasuda J, Shimizu A, Hachiya T, Shiwa Y, Tominaga T, Tanaka H, Oyama K, Tanaka R, Kawame H, Fukushima A, Ishigaki Y, Tokutomi T, Osumi N, Kobayashi T, Nagami F, Hashizume H, Arai T, Kawaguchi Y, Higuchi S, Sakaida M, Endo R, Nishizuka S, Tsuji I, Hitomi J, Nakamura M, Ogasawara K, Yaegashi N, Kinoshita K, Kure S, Sakai A, Kobayashi S, Sobue K, Sasaki M, Yamamoto M

Journal of epidemiology　31　(1)　65-76　2020年1月11日

DOI： 10.2188/jea.JE20190271 　

ISSN：0917-5040
コホート調査における代謝プロファイルの経時変化の解析

小柴生造, 元池育子, 三枝大輔, 井上仁, 菱沼英史, 青木裕一, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　92回　[1T12a-04]　2019年9月
出版者・発行元： (公社)日本生化学会
Cohort Profile: Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study): Rationale, Progress and Perspective. 国際誌査読有り

Kuriyama S, Metoki H, Kikuya M, Obara T, Ishikuro M, Yamanaka C, Nagai M, Matsubara H, Kobayashi T, Sugawara J, Tamiya G, Hozawa A, Nakaya N, Tsuchiya N, Nakamura T, Narita A, Kogure M, Hirata T, Tsuji I, Nagami F, Fuse N, Arai T, Kawaguchi Y, Higuchi S, Sakaida M, Suzuki Y, Osumi N, Nakayama K, Ito K, Egawa S, Chida K, Kodama E, Kiyomoto H, Ishii T, Tsuboi A, Tomita H, Taki Y, Kawame H, Suzuki K, Ishii N, Ogishima S, Mizuno S, Takai-Igarashi T, Minegishi N, Yasuda J, Igarashi K, Shimizu R, Nagasaki M, Tanabe O, Koshiba S, Hashizume H, Motohashi H, Tominaga T, Ito S, Tanno K, Sakata K, Shimizu A, Hitomi J, Sasaki M, Kinoshita K, Tanaka H, Kobayashi T, Kure S, Yaegashi N, Yamamoto M, Tohoku Medical Megabank Project, Study Group

International journal of epidemiology　2019年8月25日

DOI： 10.1093/ije/dyz169 　

ISSN：0300-5771
Identification of novel biomarkers of hepatocellular carcinoma by high-definition mass spectrometry: Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry and desorption electrospray ionization mass spectrometry imaging. 国際誌査読有り

Koshi Nagai, Baasanjav Uranbileg, Zhen Chen, Amane Fujioka, Takahiro Yamazaki, Yotaro Matsumoto, Hiroki Tsukamoto, Hitoshi Ikeda, Yutaka Yatomi, Hitoshi Chiba, Shu-Ping Hui, Toru Nakazawa, Ritsumi Saito, Seizo Koshiba, Junken Aoki, Daisuke Saigusa, Yoshihisa Tomioka

Rapid communications in mass spectrometry : RCM　34 Suppl 1　(Suppl 1)　e8551　2019年8月14日

DOI： 10.1002/rcm.8551 　

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RATIONALE: Hepatocellular carcinoma (HCC) is a highly malignant disease for which the development of prospective or prognostic biomarkers is urgently required. Although metabolomics is widely used for biomarker discovery, there are some bottlenecks regarding the comprehensiveness of detected features, reproducibility of methods, and identification of metabolites. In addition, information on localization of metabolites in tumor tissue is needed for functional analysis. Here, we developed a wide-polarity global metabolomics (G-Met) method, identified HCC biomarkers in human liver samples by high-definition mass spectrometry (HDMS), and demonstrated localization in cryosections using desorption electrospray ionization MS imaging (DESI-MSI) analysis. METHODS: Metabolic profiling of tumor (n = 38) and nontumor (n = 72) regions in human livers of HCC was performed by an ultrahigh-performance liquid chromatography quadrupole time-of-flight MS (UHPLC/QTOFMS) instrument equipped with a mixed-mode column. The HCC biomarker candidates were extracted by multivariate analyses and identified by matching values of the collision cross section and their fragment ions on the mass spectra obtained by HDMS. Cryosections of HCC livers, which included both tumor and nontumor regions, were analyzed by DESI-MSI. RESULTS: From the multivariate analysis, m/z 904.83 and m/z 874.79 were significantly high and low, respectively, in tumor samples and were identified as triglyceride (TG) 16:0/18:1(9Z)/20:1(11Z) and TG 16:0/18:1(9Z)/18:2(9Z,12Z) using the synthetic compounds. The TGs were clearly localized in the tumor or nontumor areas of the cryosection. CONCLUSIONS: Novel biomarkers for HCC were identified by a comprehensive and reproducible G-Met method with HDMS using a mixed-mode column. The combination analysis of UHPLC/QTOFMS and DESI-MSI revealed that the different molecular species of TGs were associated with tumor distribution and were useful for characterizing the progression of tumor cells and discovering prospective biomarkers.
Value of global metabolomics in association with diagnosis and clinicopathological factors of renal cell carcinoma. 国際誌査読有り

Tomonori Sato, Yoshihide Kawasaki, Masamitsu Maekawa, Shinya Takasaki, Daisuke Saigusa, Hideki Ota, Shuichi Shimada, Shinichi Yamashita, Koji Mitsuzuka, Hiroaki Yamaguchi, Akihiro Ito, Kengo Kinoshita, Seizo Koshiba, Nariyasu Mano, Yoichi Arai

International journal of cancer　145　(2)　484-493　2019年7月15日

DOI： 10.1002/ijc.32115 　

ISSN：0020-7136

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Renal cell carcinoma (RCC) is a malignant tumor that currently lacks clinically useful biomarkers indicative of early diagnosis or disease status. RCC has commonly been diagnosed based on imaging results. Metabolomics offers a potential technology for discovering biomarkers and therapeutic targets by comprehensive screening of metabolites from patients with various cancers. We aimed to identify metabolites associated with early diagnosis and clinicopathological factors in RCC using global metabolomics (G-Met). Tumor and nontumor tissues were sampled from 20 cases of surgically resected clear cell RCC. G-Met was performed by liquid chromatography mass spectrometry and important metabolites specific to RCC were analyzed by multivariate statistical analysis for cancer diagnostic ability based on area under the curve (AUC) and clinicopathological factors (tumor volume, pathological T stage, Fuhrman grade, presence of coagulation necrosis and distant metastasis). We identified 58 metabolites showing significantly increased levels in tumor tissues, 34 of which showed potential early diagnostic ability (AUC >0.8), but 24 did not discriminate between tumor and nontumor tissues (AUC ≤0.8). We recognized 6 pathways from 9 metabolites with AUC >0.8 and 7 pathways from 10 metabolites with AUC ≤0.8 about malignant status. Clinicopathological factors involving malignant status correlated significantly with metabolites showing AUC ≤0.8 (p = 0.0279). The tricarboxylic acid cycle (TCA) cycle, TCA cycle intermediates, nucleotide sugar pathway and inositol pathway were characteristic pathways for the malignant status of RCC. In conclusion, our study found that metabolites and their pathways allowed discrimination between early diagnosis and malignant status in RCC according to our G-Met protocol.
グローバルメタボロミクスを用いた腎癌の診断と臨床病理学的因子に関わる代謝化合物の評価

佐藤友紀, 川崎芳英, 前川正充, 高崎新也, 三枝大輔, 大田英揮, 嶋田修一, 山下慎一, 三塚浩二, 伊藤明宏, 小柴生造, 眞野成康, 荒井陽一

日本泌尿器科学会総会　107回　OP-035　2019年4月
出版者・発行元： (一社)日本泌尿器科学会総会事務局
Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. 国際誌査読有り

Yamaguchi-Kabata Y, Yasuda J, Uruno A, Shimokawa K, Koshiba S, Suzuki Y, Fuse N, Kawame H, Tadaka S, Nagasaki M, Kojima K, Katsuoka F, Kumada K, Tanabe O, Tamiya G, Yaegashi N, Kinoshita K, Yamamoto M, Kure S, Tohoku Medical Megabank Project, Study Group

Human genetics　138　(4)　389-409　2019年3月

DOI： 10.1007/s00439-019-01998-7 　

ISSN：0340-6717
Maternity Log study: a longitudinal lifelog monitoring and multiomics analysis for the early prediction of complicated pregnancy. 国際誌査読有り

Junichi Sugawara, Daisuke Ochi, Riu Yamashita, Takafumi Yamauchi, Daisuke Saigusa, Maiko Wagata, Taku Obara, Mami Ishikuro, Yoshiki Tsunemoto, Yuki Harada, Tomoko Shibata, Takahiro Mimori, Junko Kawashima, Fumiki Katsuoka, Takako Igarashi-Takai, Soichi Ogishima, Hirohito Metoki, Hiroaki Hashizume, Nobuo Fuse, Naoko Minegishi, Seizo Koshiba, Osamu Tanabe, Shinichi Kuriyama, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Masayuki Yamamoto, Satoshi Hiyama, Masao Nagasaki

BMJ open　9　(2)　e025939　2019年2月19日

DOI： 10.1136/bmjopen-2018-025939 　

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PURPOSE: A prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome. PARTICIPANTS: Pregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language. FINDINGS TO DATE: Study participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis. FUTURE PLANS: Lifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.
3.5KJPNv2: an allele frequency panel of 3552 Japanese individuals including the X chromosome. 査読有り

Tadaka S, Katsuoka F, Ueki M, Kojima K, Makino S, Saito S, Otsuki A, Gocho C, Sakurai-Yageta M, Danjoh I, Motoike IN, Yamaguchi-Kabata Y, Shirota M, Koshiba S, Nagasaki M, Minegishi N, Hozawa A, Kuriyama S, Shimizu A, Yasuda J, Fuse N, Tohoku Medical Megabank Project, Study Group, Tamiya G, Yamamoto M, Kinoshita K

Human genome variation　6　(1)　28　2019年
出版者・発行元：
DOI： 10.1038/s41439-019-0059-5 　

eISSN：2054-345X
Genome analyses for the Tohoku Medical Megabank Project toward establishment of personalized healthcare. 査読有り

Yasuda J, Kinoshita K, Katsuoka F, Danjoh I, Sakurai-Yageta M, Motoike IN, Kuroki Y, Saito S, Kojima K, Shirota M, Saigusa D, Otsuki A, Kawashima J, Yamaguchi-Kabata Y, Tadaka S, Aoki Y, Mimori T, Kumada K, Inoue J, Makino S, Kuriki M, Fuse N, Koshiba S, Tanabe O, Nagasaki M, Tamiya G, Shimizu R, Takai-Igarashi T, Ogishima S, Hozawa A, Kuriyama S, Sugawara J, Tsuboi A, Kiyomoto H, Ishii T, Tomita H, Minegishi N, Suzuki Y, Suzuki K, Kawame H, Tanaka H, Taki Y, Yaegashi N, Kure S, Nagami F, Tohoku Medical Megabank Project, Study Group, Kosaki K, Sutoh Y, Hachiya T, Shimizu A, Sasaki M, Yamamoto M

Journal of biochemistry　165　(2)　139-158　2018年11月

DOI： 10.1093/jb/mvy096 　

ISSN：0021-924X

eISSN：1756-2651
Biallelic GALM pathogenic variants cause a novel type of galactosemia 査読有り

Yoichi Wada†, Atsuo Kikuchi†, Natsuko Arai-Ichinoi†, Osamu Sakamoto†, Yusuke Takezawa, Shinya Iwasawa, Tetsuya Niihori, Hiromi Nyuzuki, Yoko Nakajima, Erika Ogawa, Mika Ishige, Hiroki Hirai, Hideo Sasai, Ryoji Fujiki, Matsuyuki Shirota, Ryo Funayama, Masayuki Yamamoto, Tetsuya Ito, Osamu Ohara, Keiko Nakayama, Yoko Aoki, Seizo Koshiba, Toshiyuki Fukao, Shigeo Kure, co-first authors, corresponding author

Genetics in Medicine　21　(6)　1286-1294　2018年10月

DOI： 10.1038/s41436-018-0340-x 　

ISSN：1098-3600

eISSN：1530-0366
メタボロームGWASによる日本人の代謝プロファイルの解析

小柴生造, 元池育子, 三枝大輔, 井上仁, 青木裕一, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　91回　[3T14a-314)]　2018年9月
出版者・発行元： (公社)日本生化学会
Metabolomic changes in the mouse retina after optic nerve injury. 国際誌査読有り

Kota Sato, Daisuke Saigusa, Ritsumi Saito, Amane Fujioka, Yurika Nakagawa, Koji M Nishiguchi, Taiki Kokubun, Ikuko N Motoike, Kazuichi Maruyama, Kazuko Omodaka, Yukihiro Shiga, Akira Uruno, Seizo Koshiba, Masayuki Yamamoto, Toru Nakazawa

Scientific reports　8　(1)　11930-11930　2018年8月9日

DOI： 10.1038/s41598-018-30464-z 　

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In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.
Detection of novel metabolite for roxadustat doping by global metabolomics. 国際誌

Daisuke Saigusa, Norio Suzuki, Yotaro Matsumoto, Keiko Umeda, Yoshihisa Tomioka, Seizo Koshiba, Masayuki Yamamoto

Journal of biochemistry　163　(6)　e1　2018年6月1日

DOI： 10.1093/jb/mvy036 　
Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. 国際誌査読有り

Seizo Koshiba, Ikuko Motoike, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Yasutake Katoh, Fumiki Katsuoka, Inaho Danjoh, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Soichi Ogishima, Nobuo Fuse, Shigeo Kure, Gen Tamiya, Osamu Tanabe, Jun Yasuda, Kengo Kinoshita, Masayuki Yamamoto

Genes to cells : devoted to molecular & cellular mechanisms　23　(6)　406-417　2018年6月

DOI： 10.1111/gtc.12588 　

ISSN：1356-9597

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Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population-based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies.
ゲノミクスを基盤とした生活習慣病解析最前線ゲノム情報と連携した日本人多層オミックス参照パネルの意義

小柴生造, 元池育子, 三枝大輔, 井上仁, 城田松之, 青木裕一, 田高周, 斎藤智, 木下賢吾, 山本雅之

糖尿病　61　(Suppl.1)　S-48　2018年4月
出版者・発行元： (一社)日本糖尿病学会
ISSN：0021-437X

eISSN：1881-588X
Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals. 国際誌査読有り

Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

Journal of human genetics　63　(2)　213-230　2018年2月

DOI： 10.1038/s10038-017-0347-1 　

ISSN：1434-5161

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Clarifying allele frequencies of disease-related genetic variants in a population is important in genomic medicine; however, such data is not yet available for the Japanese population. To estimate frequencies of actionable pathogenic variants in the Japanese population, we examined the reported pathological variants in genes recommended by the American College of Medical Genetics and Genomics (ACMG) in our reference panel of genomic variations, 2KJPN, which was created by whole-genome sequencing of 2049 individuals of the resident cohort of the Tohoku Medical Megabank Project. We searched for pathogenic variants in 2KJPN for 57 autosomal ACMG-recommended genes responsible for 26 diseases and then examined their frequencies. By referring to public databases of pathogenic variations, we identified 143 reported pathogenic variants in 2KJPN for the 57 ACMG recommended genes based on a classification system. At the individual level, 21% of the individuals were found to have at least one reported pathogenic allele. We then conducted a literature survey to review the variants and to check for evidence of pathogenicity. Our results suggest that a substantial number of people have reported pathogenic alleles for the ACMG genes, and reviewing variants is indispensable for constructing the information infrastructure of genomic medicine for the Japanese population.
jMorp: Japanese Multi Omics Reference Panel. 国際誌査読有り

Shu Tadaka, Daisuke Saigusa, Ikuko N Motoike, Jin Inoue, Yuichi Aoki, Matsuyuki Shirota, Seizo Koshiba, Masayuki Yamamoto, Kengo Kinoshita

Nucleic acids research　46　(D1)　D551-D557-D557　2018年1月4日

DOI： 10.1093/nar/gkx978 　

ISSN：0305-1048

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We developed jMorp, a new database containing metabolome and proteome data for plasma obtained from >5000 healthy Japanese volunteers from the Tohoku Medical Megabank Cohort Study, which is available at https://jmorp.megabank.tohoku.ac.jp. Metabolome data were measured by proton nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS), while proteome data were obtained by nanoLC-MS. We released the concentration distributions of 37 metabolites identified by NMR, distributions of peak intensities of 257 characterized metabolites by LC-MS, and observed frequencies of 256 abundant proteins. Additionally, correlation networks for the metabolites can be observed using an interactive network viewer. Compared with some existing databases, jMorp has some unique features: (i) Metabolome data were obtained using a single protocol in a single institute, ensuring that measurement biases were significantly minimized; (ii) The database contains large-scale data for healthy volunteers with various health records and genome data and (iii) Correlations between metabolites can be easily observed using the graphical viewer. Metabolites data are becoming important intermediate markers for evaluating the health states of humans, and thus jMorp is an outstanding resource for a wide range of researchers, particularly those in the fields of medical science, applied molecular biology, and biochemistry.
高精度日本人多層オミックス参照パネルの提供

小柴生造, 元池育子, 三枝大輔, 井上仁, 城田松之, 斎藤智, 木下賢吾, 山本雅之

生命科学系学会合同年次大会　2017年度　[3P-1369]　2017年12月
出版者・発行元：生命科学系学会合同年次大会運営事務局
The Tohoku Medical Megabank Project: Design and Mission 査読有り

Shinichi Kuriyama, Nobuo Yaegashi, Fuji Nagami, Tomohiko Arai, Yoshio Kawaguchi, Noriko Osumi, Masaki Sakaida, Yoichi Suzuki, Keiko Nakayama, Hiroaki Hashizume, Gen Tamiya, Hiroshi Kawame, Kichiya Suzuki, Atsushi Hozawa, Naoki Nakaya, Masahiro Kikuya, Hirohito Metoki, Ichiro Tsuji, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Akito Tsuboi, Shinichi Egawa, Kiyoshi Ito, Koichi Chida, Tadashi Ishii, Hiroaki Tomita, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Jun Yasuda, Kazuhiko Igarashi, Ritsuko Shimizu, Masao Nagasaki, Seizo Koshiba, Kengo Kinoshita, Soichi Ogishima, Takako Takai-Igarashi, Teiji Tominaga, Osamu Tanabe, Noriaki Ohuchi, Toru Shimosegawa, Shigeo Kure, Hiroshi Tanaka, Sadayoshi Ito, Jiro Hitomi, Kozo Tanno, Motoyuki Nakamura, Kuniaki Ogasawara, Seiichiro Kobayashi, Kiyomi Sakata, Mamoru Satoh, Atsushi Shimizu, Makoto Sasaki, Ryujin Endo, Kenji Sobue, Masayuki Yamamoto

JOURNAL OF EPIDEMIOLOGY　26　(9)　493-511　2016年9月

DOI： 10.2188/jea.JE20150268 　

ISSN：0917-5040
The structural origin of metabolic quantitative diversity 査読有り

Seizo Koshiba, Ikuko Motoike, Kaname Kojima, Takanori Hasegawa, Matsuyuki Shirota, Tomo Saito, Daisuke Saigusa, Inaho Danjoh, Fumiki Katsuoka, Soichi Ogishima, Yosuke Kawai, Yumi Yamaguchi-Kabata, Miyuki Sakurai, Sachiko Hirano, Junichi Nakata, Hozumi Motohashi, Atsushi Hozawa, Shinichi Kuriyama, Naoko Minegishi, Masao Nagasaki, Takako Takai-Igarashi, Nobuo Fuse, Hideyasu Kiyomoto, Junichi Sugawara, Yoichi Suzuki, Shigeo Kure, Nobuo Yaegashi, Osamu Tanabe, Kengo Kinoshita, Jun Yasuda, Masayuki Yamamoto

SCIENTIFIC REPORTS　6　31463　2016年8月

DOI： 10.1038/srep31463 　

ISSN：2045-2322
Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery 査読有り

Daisuke Saigusa, Yasunobu Okamura, Ikuko N. Motoike, Yasutake Katoh, Yasuhiro Kurosawa, Reina Saijyo, Seizo Koshiba, Jun Yasuda, Hozumi Motohashi, Junichi Sugawara, Osamu Tanabe, Kengo Kinoshita, Masayuki Yamamoto

PLOS ONE　11　(8)　e0160555　2016年8月

DOI： 10.1371/journal.pone.0160555 　

ISSN：1932-6203
東北メディカル・メガバンク機構における血漿プロテオミクス解析

城田松之, 加藤恭丈, 元池育子, 木下賢吾, 小柴生造

日本プロテオーム学会大会要旨集　2016　98-98　2016年
出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）
DOI： 10.14889/jhupo.2016.0.98.0 　
Japanese multi omics reference panel 査読有り

Seizo Koshiba

Seikagaku　88　(1)　25-30　2016年
出版者・発行元： Japanese Biochemical Society
DOI： 10.14952/SEIKAGAKU.2016.880025 　

ISSN：2189-0544 0037-1017
Stable isotope labeling strategy based on coding theory 査読有り

Takuma Kasai, Seizo Koshiba, Jun Yokoyama, Takanori Kigawa

JOURNAL OF BIOMOLECULAR NMR　63　(2)　213-221　2015年10月

DOI： 10.1007/s10858-015-9978-8 　

ISSN：0925-2738

eISSN：1573-5001
Identification of key neoculin residues responsible for the binding and activation of the sweet taste receptor 査読有り

Taichi Koizumi, Tohru Terada, Ken-ichiro Nakajima, Masaki Kojima, Seizo Koshiba, Yoshitaka Matsumura, Kohei Kaneda, Tomiko Asakura, Akiko Shimizu-Ibuka, Keiko Abe, Takumi Misaka

SCIENTIFIC REPORTS　5　12947　2015年8月

DOI： 10.1038/srep12947 　

ISSN：2045-2322
Solution structures of the DNA-binding domains of immune-related zinc-finger protein ZFAT 査読有り

Naoya Tochio, Takashi Umehara, Kazuhiko Nakabayashi, Misao Yoneyama, Kengo Tsuda, Mikako Shirouzu, Seizo Koshiba, Satoru Watanabe, Takanori Kigawa, Takehiko Sasazuki, Senji Shirasawa, Shigeyuki Yokoyama

Journal of Structural and Functional Genomics　16　(2)　55-65　2015年6月15日
出版者・発行元： Springer Netherland
DOI： 10.1007/s10969-015-9196-3 　

ISSN：1570-0267 1345-711X
Solution structure and siRNA-mediated knockdown analysis of the mitochondrial disease-related protein C12orf65 査読有り

Hiroyuki Kogure, Yusuke Hikawa, Mamoru Hagihara, Naoya Tochio, Seizo Koshiba, Yusuke Inoue, Peter Guentert, Takanori Kigawa, Shigeyuki Yokoyama, Nobukazu Nameki

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　80　(11)　2629-2642　2012年11月

DOI： 10.1002/prot.24152 　

ISSN：0887-3585
Structural basis for mutual relief of the Rac guanine nucleotide exchange factor DOCK2 and its partner ELMO1 from their autoinhibited forms 査読有り

Kyoko Hanawa-Suetsugu, Mutsuko Kukimoto-Niino, Chiemi Mishima-Tsumagari, Ryogo Akasaka, Noboru Ohsawa, Shun-ichi Sekine, Takuhiro Ito, Naoya Tochio, Seizo Koshiba, Takanori Kigawa, Takaho Terada, Mikako Shirouzu, Akihiko Nishikimi, Takehito Uruno, Tomoya Katakai, Tatsuo Kinashi, Daisuke Kohda, Yoshinori Fukui, Shigeyuki Yokoyama

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　109　(9)　3305-3310　2012年2月

DOI： 10.1073/pnas.1113512109 　

ISSN：0027-8424
ZF21 Protein, a Regulator of the Disassembly of Focal Adhesions and Cancer Metastasis, Contains a Novel Noncanonical Pleckstrin Homology Domain 査読有り

Makoto Nagano, Daisuke Hoshino, Seizo Koshiba, Takuya Shuo, Naohiko Koshikawa, Tadashi Tomizawa, Fumiaki Hayashi, Naoya Tochio, Takushi Harada, Toshifumi Akizawa, Satoru Watanabe, Noriko Handa, Mikako Shirouzu, Takanori Kigawa, Shigeyuki Yokoyama, Motoharu Seiki

JOURNAL OF BIOLOGICAL CHEMISTRY　286　(36)　31598-31609　2011年9月

DOI： 10.1074/jbc.M110.199430 　

ISSN：0021-9258

eISSN：1083-351X
Phosphatidylinositol monophosphate-binding interface in the oomycete RXLR effector AVR3a is required for its stability in host cells to modulate plant immunity 査読有り

Takashi Yaeno, Hua Li, Angela Chaparro-Garcia, Sebastian Schornack, Seizo Koshiba, Satoru Watanabe, Takanori Kigawa, Sophien Kamoun, Ken Shirasu

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　108　(35)　14682-14687　2011年8月

DOI： 10.1073/pnas.1106002108 　

ISSN：0027-8424
NMR Solution Structure of Human Vaccinia-related Kinase 1 (VRK1) Reveals the C-terminal Tail Essential for Its Structural Stability and Autocatalytic Activity 査読有り

Joon Shin, Goutam Chakraborty, Nagakumar Bharatham, CongBao Kang, Naoya Tochio, Seizo Koshiba, Takanori Kigawa, Wanil Kim, Kyong-Tai Kim, Ho Sup Yoon

JOURNAL OF BIOLOGICAL CHEMISTRY　286　(25)　22131-22138　2011年6月

DOI： 10.1074/jbc.M110.200162 　

ISSN：0021-9258
A practical method for cell-free protein synthesis to avoid stable isotope scrambling and dilution 査読有り

Jun Yokoyama, Takayoshi Matsuda, Seizo Koshiba, Naoya Tochio, Takanori Kigawa

ANALYTICAL BIOCHEMISTRY　411　(2)　223-229　2011年4月

DOI： 10.1016/j.ab.2011.01.017 　

ISSN：0003-2697

eISSN：1096-0309
An economical method for producing stable-isotope labeled proteins by the E. coli cell-free system 査読有り

Jun Yokoyama, Takayoshi Matsuda, Seizo Koshiba, Takanori Kigawa

JOURNAL OF BIOMOLECULAR NMR　48　(4)　193-201　2010年12月

DOI： 10.1007/s10858-010-9455-3 　

ISSN：0925-2738
Solution Structure of the Catalytic Domain of the Mitochondrial Protein ICT1 That Is Essential for Cell Vitality 査読有り

Yoshihiro Handa, Yusuke Hikawa, Naoya Tochio, Hiroyuki Kogure, Makoto Inoue, Seizo Koshiba, Peter Guentert, Yusuke Inoue, Takanori Kigawa, Shigeyuki Yokoyama, Nobukazu Nameki

JOURNAL OF MOLECULAR BIOLOGY　404　(2)　260-273　2010年11月

DOI： 10.1016/j.jmb.2010.09.033 　

ISSN：0022-2836
Solution Structure of Histone Chaperone ANP32B: Interaction with Core Histones H3-H4 through Its Acidic Concave Domain 査読有り

Naoya Tochio, Takashi Umehara, Yoshiko Munemasa, Toru Suzuki, Shin Sato, Kengo Tsuda, Seizo Koshiba, Takanori Kigawa, Ryozo Nagai, Shigeyuki Yokoyama

JOURNAL OF MOLECULAR BIOLOGY　401　(1)　97-114　2010年8月

DOI： 10.1016/j.jmb.2010.06.005 　

ISSN：0022-2836
Solution structure of the C-terminal DUF1000 domain of the human thioredoxin-like 1 protein 査読有り

Alexander K. Goroncy, Seizo Koshiba, Naoya Tochio, Tadashi Tomizawa, Makoto Inoue, Akiko Tanaka, Sumio Sugano, Takanori Kigawa, Shigeyuki Yokoyama

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　78　(9)　2176-2180　2010年7月

DOI： 10.1002/prot.22719 　

ISSN：0887-3585
The NMR solution structures of the five constituent cold-shock domains (CSD) of the human UNR (upstream of N-ras) protein 査読有り

Alexander K. Goroncy, Seizo Koshiba, Naoya Tochio, Tadashi Tomizawa, Makato Inoue, Satoru Watanabe, Takushi Harada, Akiko Tanaka, Osamu Ohara, Takanori Kigawa, Shigeyuki Yokoyama

Journal of Structural and Functional Genomics　11　(2)　181-188　2010年6月

DOI： 10.1007/s10969-010-9081-z 　

ISSN：1345-711X
Structural basis for the recognition of nucleophosmin-anaplastic lymphoma kinase oncoprotein by the phosphotyrosine binding domain of Suc1-associated neurotrophic factor-induced tyrosine-phosphorylated target-2 査読有り

Seizo Koshiba, Hua Li, Yoko Motoda, Tadashi Tomizawa, Takuma Kasai, Naoya Tochio, Takashi Yabuki, Takushi Harada, Satoru Watanabe, Akiko Tanaka, Mikako Shirouzu, Takanori Kigawa, Tadashi Yamamoto, Shigeyuki Yokoyama

Journal of Structural and Functional Genomics　11　(2)　125-141　2010年6月

DOI： 10.1007/s10969-010-9091-x 　

ISSN：1345-711X
S-33 nuclear magnetic resonance spectroscopy of biological samples obtained with a laboratory model S-33 cryogenic probe 査読有り

Fumio Hobo, Masato Takahashi, Yuta Saito, Naoki Sato, Tomoaki Takao, Seizo Koshiba, Hideaki Maeda

REVIEW OF SCIENTIFIC INSTRUMENTS　81　(5)　054302　2010年5月

DOI： 10.1063/1.3424853 　

ISSN：0034-6748
NMR solution structures of actin depolymerizing factor homology domains 査読有り

Alexander K. Goroncy, Seizo Koshiba, Naoya Tochio, Tadashi Tomizawa, Manami Sato, Makato Inoue, Satoru Watanabe, Yoshihide Hayashizaki, Akiko Tanaka, Takanori Kigawa, Shigeyuki Yokoyama

PROTEIN SCIENCE　18　(11)　2384-2392　2009年11月

DOI： 10.1002/pro.248 　

ISSN：0961-8368

eISSN：1469-896X
Solution structure of the GUCT domain from human RNA helicase II/Gu beta reveals the RRM fold, but implausible RNA interactions 査読有り

Satoshi Ohnishi, Kimmo Paakkonen, Seizo Koshiba, Naoya Tochio, Manami Sato, Naohiro Kobayashi, Takushi Harada, Satoru Watanabe, Yutaka Muto, Peter Guntert, Akiko Tanaka, Takanori Kigawa, Shigeyuki Yokoyama

PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS　74　(1)　133-144　2009年1月

DOI： 10.1002/prot.22138 　

ISSN：0887-3585

eISSN：1097-0134
Structure of the C-terminal phosphotyrosine interaction domain of Fe65L1 complexed with the cytoplasmic tail of amyloid precursor protein reveals a novel peptide binding mode 査読有り

Hua Li, Seizo Koshiba, Fumiaki Hayashi, Naoya Tochio, Tadashi Tomizawa, Takuma Kasai, Takashi Yabuki, Yoko Motoda, Takushi Harada, Satoru Watanabe, Makoto Inoue, Yoshihide Hayashizaki, Akiko Tanaka, Takanori Kigawa, Shigeyuki Yokoyama

JOURNAL OF BIOLOGICAL CHEMISTRY　283　(40)　27165-27178　2008年10月

DOI： 10.1074/jbc.M803892200 　

ISSN：0021-9258

eISSN：1083-351X
Structural basis for controlling the dimerization and stability of the WW domains of an atypical subfamily 査読有り

Satoshi Ohnishi, Naoya Tochio, Tadashi Tomizawa, Ryogo Akasaka, Takushi Harada, Eiko Seki, Manami Sato, Satoru Watanabe, Yukiko Fujikura, Seizo Koshiba, Takaho Terada, Mikako Shirouzu, Akiko Tanaka, Takanori Kigawa, Shigeyuki Yokoyama

PROTEIN SCIENCE　17　(9)　1531-1541　2008年9月

DOI： 10.1110/ps.035329.108 　

ISSN：0961-8368

eISSN：1469-896X
Basic folded and low-populated locally disordered conformers of SUMO-2 characterized by NMR spectroscopy at varying pressures 査読有り

Ryo Kitahara, Chenhua Zhao, Kohei Saito, Seizo Koshiba, Makoto Ioune, Takanori Kigawa, Shigeyuki Yokoyama, Kazuyuki Akasaka

BIOCHEMISTRY　47　(1)　30-39　2008年1月

DOI： 10.1021/bi7014458 　

ISSN：0006-2960
KUJIRA, a package of integrated modules for systematic and interactive analysis of NMR data directed to high-throughput NMR structure studies 査読有り

Naohiro Kobayashi, Junji Iwahara, Seizo Koshiba, Tadashi Tomizawa, Naoya Tochio, Peter Guentert, Takanori Kigawa, Shigeyuki Yokoyama

JOURNAL OF BIOMOLECULAR NMR　39　(1)　31-52　2007年9月

DOI： 10.1007/s10858-007-9175-5 　

ISSN：0925-2738
Structural and functional differences of SWIRM domain subtypes 査読有り

Misao Yoneyama, Naoya Tochio, Takashi Umehara, Seizo Koshiba, Makoto Inoue, Takashi Yabuki, Masaaki Aoki, Eiko Seki, Takayoshi Matsuda, Satoru Watanabe, Yasuko Tomo, Yuji Nishimura, Takushi Harada, Takaho Terada, Mikako Shirouzu, Yoshihide Hayashizaki, Osamu Ohara, Akiko Tanaka, Takanori Kigawa, Shigeyuki Yokoyama

JOURNAL OF MOLECULAR BIOLOGY　369　(1)　222-238　2007年5月

DOI： 10.1016/j.jmb.2007.03.027 　

ISSN：0022-2836

eISSN：1089-8638
Improving cell-free protein synthesis for stable-isotope labeling 査読有り

Takayoshi Matsuda, Seizo Koshiba, Naoya Tochio, Eiko Seki, Noriyuki Iwasaki, Takashi Yabuki, Makoto Inoue, Shigeyuki Yokoyama, Takanori Kigawa

JOURNAL OF BIOMOLECULAR NMR　37　(3)　225-229　2007年3月

DOI： 10.1007/s10858-006-9127-5 　

ISSN：0925-2738
Solution structure of an atypical WW domain in a novel beta-clam-like dimeric form 査読有り

Satoshi Ohnishi, Peter Guntert, Seizo Koshiba, Tadashi Tomizawa, Ryogo Akasaka, Naoya Tochio, Manami Sato, Makoto Inoue, Takushi Harada, Satoru Watanabe, Akiko Tanaka, Mikako Shirouzu, Takanori Kigawa, Shigeyuki Yokoyama

FEBS LETTERS　581　(3)　462-468　2007年2月

DOI： 10.1016/j.febslet.2007.01.008 　

ISSN：0014-5793
3P067 WWドメインに見るタンパク質二量化の制御とデザイン(蛋白質(物性(安定性、折れ畳みなど)),口頭発表,第45回日本生物物理学会年会)

大西哲, 栃尾直哉, 赤坂領吾, 原田拓志, 富澤忠, 佐藤真奈美, 小柴生造, 渡部暁, 関英子, 藤倉由紀子, 白水美香子, 木川隆則, 横山茂之

生物物理　47　S219　2007年
出版者・発行元：一般社団法人日本生物物理学会
DOI： 10.2142/biophys.47.S219_4 　
2P039 1配列で二つの構造? : ヒトのtripartite motif 39 proteinのB-boxドメインの溶液構造(蛋白質(構造・構造機能相関),ポスター発表,第45回日本生物物理学会年会)

富澤忠, 小柴生造, 渡部暁, 原田拓志, 木川隆則, 横山茂之

生物物理　47　S122　2007年
出版者・発行元：一般社団法人日本生物物理学会
DOI： 10.2142/biophys.47.S122_4 　
1P059 統合管理型NMRデータ解析ソフトウエアKUJIRA : グラフデータ構造の導入によるインテラクティブな解析(蛋白質(計測解析の方法論),ポスター発表,第45回日本生物物理学会年会)

小林直宏, 栃尾尚哉, 富沢忠, 小柴生造, 木川隆則, 横山茂之

生物物理　47　S38　2007年
出版者・発行元：一般社団法人日本生物物理学会
DOI： 10.2142/biophys.47.S38_2 　
Solution structure of the kinase-associated domain 1 of mouse microtubule-associated protein/microtubule affinity-regulating kinase 3 査読有り

Naoya Tochio, Seizo Koshiba, Naohiro Kobayashi, Makoto Inoue, Takashi Yabuki, Masaaki Aoki, Eiko Seki, Takayoshi Matsuda, Yasuko Tomo, Yoko Motoda, Atsuo Kobayashi, Akiko Tanaka, Yoshihide Hayashizaki, Takaho Terada, Mikako Shirouzu, Takanori Kigawa, Shigeyuki Yokoyama

PROTEIN SCIENCE　15　(11)　2534-2543　2006年11月

DOI： 10.1110/ps.062391106 　

ISSN：0961-8368
P-403 STRUCTURE-BASED MOLECULAR INTERACTION ANALYSIS BETWEEN HUMAN ACYL-COENZYME A BINDING PROTEINS AND ACYL-COENZYME A DERIVATIVES

MOMEN A.Z.M. Ruhul, TSUBOTA Yusuke, ONUKI Hiroyuki, YASUMURO Kenichi, SATOU Kazuhito, ABE Takamasa, HAMADA Toshiyuki, HAYASHI Fumiaki, SAITO Kohei, KOSHIBA Seizo, KIGAWA Takanori, YOKOYAMA Shigeyuki, HIROTA Hiroshi

International Symposium on the Chemistry of Natural Products　2006　"P-403"　2006年7月23日
出版者・発行元：天然有機化合物討論会
DOI： 10.24496/intnaturalprod.2006.0__P-403_ 　
Cell-free synthesis of zinc-binding proteins 査読有り

Takayoshi Matsuda, Takanori Kigawa, Seizo Koshiba, Makoto Inoue, Masaaki Aoki, Kazuhiko Yamasaki, Motoaki Seki, Kazuo Shinozaki, Shigeyuki Yokoyama

Journal of Structural and Functional Genomics　7　(2)　93-100　2006年6月

DOI： 10.1007/s10969-006-9012-1 　

ISSN：1345-711X
Solution structure of the SWIRM domain of human histone demethylase LSD1 査読有り

N Tochio, T Umehara, S Koshiba, M Inoue, T Yabuki, M Aoki, E Seki, S Watanabe, Y Tomo, M Hanada, M Ikari, M Sato, T Terada, T Nagase, O Ohara, M Shirouzu, A Tanaka, T Kigawa, S Yokoyama

STRUCTURE　14　(3)　457-468　2006年3月

DOI： 10.1016/j.str.2005.12.004 　

ISSN：0969-2126
Solution structure of the mouse enhancer of rudimentary protein reveals a novel fold 査読有り

H Li, M Inoue, T Yabuki, M Aoki, E Seki, T Matsuda, E Nunokawa, Y Motoda, A Kobayashi, T Terada, M Shirouzu, S Koshiba, YJ Lin, P Guntert, H Suzuki, Y Hayashizaki, T Kigawa, S Yokoyama

JOURNAL OF BIOMOLECULAR NMR　32　(4)　329-334　2005年8月

DOI： 10.1007/s10858-005-7959-z 　

ISSN：0925-2738
Solution structure of the Src homology 2 domain from the human feline sarcoma oncogene Fes 査読有り

A Scott, D Pantoja-Uceda, S Koshiba, M Inoue, T Kigawa, T Terada, M Shirouzu, A Tanaka, S Sugano, S Yokoyama, PG Guntert

JOURNAL OF BIOMOLECULAR NMR　31　(4)　357-361　2005年4月

DOI： 10.1007/s10858-005-0946-6 　

ISSN：0925-2738
Solution structure of the PWWP domain of the hepatoma-derived growth factor family 査読有り

N Nameki, N Tochio, S Koshiba, M Inoue, T Yabuki, M Aoki, E Seki, T Matsuda, Y Fujikura, M Saito, M Ikari, M Watanabe, T Terada, M Shirouzu, M Yoshida, H Hirota, A Tanaka, Y Hayashizaki, P Guntert, T Kigawa, S Yokoyama

PROTEIN SCIENCE　14　(3)　756-764　2005年3月

DOI： 10.1110/ps.04975305 　

ISSN：0961-8368
3P024 ヒト由来SRC-like Adopter Protein (SLAP)のSH3ドメインの溶液構造から明らかになった新しい分子認識機構(蛋白質 A) 構造))

大西哲, 栃尾尚哉, 佐藤真奈美, 小柴生造, 行木信一, 井上真, 木川隆則, 横山茂之

生物物理　45　S209　2005年
出版者・発行元：一般社団法人日本生物物理学会
DOI： 10.2142/biophys.45.S209_4 　
2P021 Solution structures of six flbronectin type III domains of human Neogenin(蛋白質 A) 構造))

栃尾尚哉, 笹川彩, 小柴生造, 井上真, 木川隆則, 横山茂之

生物物理　45　S125　2005年
出版者・発行元：一般社団法人日本生物物理学会
DOI： 10.2142/biophys.45.S125_1 　
Solution structure of the rhodanese homology domain At4g01050(175-295) from Arabidopsis thaliana 査読有り

D Pantoja-Uceda, B Lopez-Mendez, S Koshiba, M Inoue, T Kigawa, T Terada, M Shirouzu, A Tanaka, M Seki, K Shinozaki, S Yokoyama, P Guntert

PROTEIN SCIENCE　14　(1)　224-230　2005年1月

DOI： 10.1110/ps.041138705 　

ISSN：0961-8368
Letter to the Editor: NMR assignment of the SH2 domain from the human feline sarcoma oncogene FES 査読有り

A Scott, D Pantoja-Uceda, S Koshiba, M Inoue, T Kigawa, T Terada, M Shirouzu, A Tanaka, S Sugano, S Yokoyama, P Guntert

JOURNAL OF BIOMOLECULAR NMR　30　(4)　463-464　2004年12月

DOI： 10.1007/s10858-004-5432-z 　

ISSN：0925-2738
The CAP-Gly domain with the proline-rich of CYLD associates sequence in NEMO/IKK gamma 査読有り

K Saito, T Kigawa, S Koshiba, K Sato, Y Matsuo, A Sakamoto, T Takagi, M Shirouzu, T Yabuki, E Nunokawa, E Seki, T Matsuda, M Aoki, Y Miyata, N Hirakawa, M Inoue, T Terada, T Nagase, R Kikuno, M Nakayama, O Ohara, A Tanaka, S Yokoyama

STRUCTURE　12　(9)　1719-1728　2004年9月

DOI： 10.1016/j.str.2004.07.012 　

ISSN：0969-2126
Solution structure of the RWD domain of the mouse GCN2 protein 査読有り

N Nameki, M Yoneyama, S Koshiba, N Tochio, M Inoue, E Seki, T Matsuda, Y Tomo, T Harada, K Saito, N Kobayashi, T Yabuki, M Aoki, E Nunokawa, N Matsuda, N Sakagami, T Terada, M Shirouzu, M Yoshida, H Hirota, T Osanai, A Tanaka, T Arakawa, P Carninci, J Kawai, Y Hayashizaki, K Kinoshita, P Guntert, T Kigawa, S Yokoyama

PROTEIN SCIENCE　13　(8)　2089-2100　2004年8月

DOI： 10.1110/ps.04751804 　

ISSN：0961-8368
Letter to the Editor: NMR assignment of the hypothetical ENTH-VHS domain At3g16270 from Arabidopsis thaliana 査読有り

B Lopez-Mendez, D Pantoja-Uceda, T Tomizawa, S Koshiba, T Kigawa, M Shirouzu, T Terada, M Inoue, T Yabuki, M Aoki, E Seki, T Matsuda, H Hirota, M Yoshida, A Tanaka, T Osanai, M Seki, K Shinozaki, S Yokoyama, P Guntert

JOURNAL OF BIOMOLECULAR NMR　29　(2)　205-206　2004年6月

DOI： 10.1023/B:JNMR.0000019239.44783.66 　

ISSN：0925-2738
Letter to the Editor: NMR assignment of the hypothetical rhodanese domain At4g01050 from Arabidopsis thaliana 査読有り

D Pantoja-Uceda, B Lopez-Mendez, S Koshiba, T Kigawa, M Shirouzu, T Terada, M Inoue, T Yabuki, M Aoki, E Seki, T Matsuda, H Hirota, M Yoshida, A Tanaka, T Osanai, M Seki, K Shinozaki, S Yokoyama, P Guntert

JOURNAL OF BIOMOLECULAR NMR　29　(2)　207-208　2004年6月

DOI： 10.1023/B:JNMR.0000019241.66789.c3 　

ISSN：0925-2738
Solution structure of the SEA domain from the murine homologue of ovarian cancer antigen CA125 (MUC16) 査読有り

T Maeda, M Inoue, S Koshiba, T Yabuki, M Aoki, E Nunokawa, E Seki, T Matsuda, Y Motoda, A Kobayashi, F Hiroyasu, M Shirouzu, T Terada, N Hayami, Y Ishizuka, N Shinya, A Tatsuguchi, M Yoshida, H Hirota, Y Matsuo, K Tani, T Arakawa, P Carninci, J Kawai, Y Hayashizaki, T Kigawa, S Yokoyama

JOURNAL OF BIOLOGICAL CHEMISTRY　279　(13)　13174-13182　2004年3月

DOI： 10.1074/jbc.M309417200 　

ISSN：0021-9258
Solution structure of a BolA-like protein from Mus musculus 査読有り

T Kasai, M Inoue, S Koshiba, T Yabuki, M Aoki, E Nunokawa, E Seki, T Matsuda, N Matsuda, Y Tomo, M Shirouzu, T Terada, N Obayashi, H Hamana, N Shinya, A Tatsuguchi, S Yasuda, M Yoshida, H Hirota, Y Matsuo, K Tani, H Suzuki, T Arakawa, P Carninci, J Kawai, Y Hayashizaki, T Kigawa, S Yokoyama

PROTEIN SCIENCE　13　(2)　545-548　2004年2月

DOI： 10.1110/ps.03401004 　

ISSN：0961-8368
Solution structure of the DFF-C domain of DFF45/ICAD. A structural basis for the regulation of apoptotic DNA fragmentation 査読有り

K Fukushima, J Kikuchi, S Koshiba, T Kigawa, Y Kuroda, S Yokoyama

JOURNAL OF MOLECULAR BIOLOGY　321　(2)　317-327　2002年8月

DOI： 10.1016/S0022-2836(02)00588-0 　

ISSN：0022-2836
[High-throughput NMR structure determination: The present and the future]. 査読有り

Hatanaka H, Koshiba S, Kikuchi J, Kigawa T, Yokoyama S

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme　47　(8 Suppl)　1038-1044　2002年6月

ISSN：0039-9450
Solution structure of the epsin N-terminal homology (ENTH) domain of human epsin 査読有り

Seizo Koshiba, Takanori Kigawa, Akira Kikuchi, Shigeyuki Yokoyama

Journal of Structural and Functional Genomics　2　(1)　1-8　2002年

DOI： 10.1023/A:1011397007366 　

ISSN：1345-711X
Characterization of acyl-CoA-binding protein (ACBP) in the pheromone gland of the silkworm, Bombyx mori 査読有り

Shogo Matsumoto, Toyoshi Yoshiga, Norihiro Yokoyama, Masashi Iwanaga, Seizo Koshiba, Takanori Kigawa, Hiroshi Hirota, Shigeyuki Yokoyama, Kazuhiro Okano, Kazuei Mita, Toru Shimada, Sadahiro Tatsuki

Insect Biochemistry and Molecular Biology　31　(6-7)　603-609　2001年4月27日

DOI： 10.1016/S0965-1748(00)00165-X 　

ISSN：0965-1748
Role of the ENTH domain in phosphatidylinositol-4,5-bisphosphate binding and endocytosis 査読有り

T Itoh, S Koshiba, T Kigawa, A Kikuchi, S Yokoyama, T Takenawa

SCIENCE　291　(5506)　1047-1051　2001年2月

DOI： 10.1126/science.291.5506.1047 　

ISSN：0036-8075
Mouse myosin X: Molecular architecture and tissue expression as revealed by northern blot and in situ hybridization analyses 査読有り

S Yonezawa, A Kimura, S Koshiba, S Masaki, T Ono, A Hanai, S Sonta, T Kageyama, T Takahashi, A Moriyama

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS　271　(2)　526-533　2000年5月

DOI： 10.1006/bbrc.2000.2669 　

ISSN：0006-291X
[Structural biology for PH and other domains involved in signal transduction] 査読有り

Koshiba S, Yokoyama S

Tanpakushitsu Kakusan Koso　44　(4 Suppl)　368-379　1999年3月

ISSN：0039-9450
2PA010 EBINのMPHドメインのNMRによる構造解析

小柴生造, 木川隆則, 菊池章, 横山茂之

生物物理　39　S103　1999年
出版者・発行元：一般社団法人日本生物物理学会
DOI： 10.2142/biophys.39.S103_2 　

ISSN：0582-4052
Solution structure of the Eps15 homology domain of a human POB1 (partner of RalBP1) 査読有り

S Koshiba, T Kigawa, J Iwahara, A Kikuchi, S Yokoyama

FEBS LETTERS　442　(2-3)　138-142　1999年1月

DOI： 10.1016/S0014-5793(98)01644-5 　

ISSN：0014-5793
The solution structure of the pleckstrin homology domain of mouse son-of-sevenless 1 (mSos1) 査読有り

S Koshiba, T Kigawa, JH Kim, M Shirouzu, D Bowtell, S Yokoyama

JOURNAL OF MOLECULAR BIOLOGY　269　(4)　579-591　1997年6月

DOI： 10.1006/jmbi.1997.1041 　

ISSN：0022-2836

︎全件表示 ︎最初の5件までを表示

MISC 44

GC-MS/MSによるダプロデュスタット服用マウスの血漿および尿中メタボローム解析

内田新菜, 中井琢, 福内友子, 山岡法子, 小柴生造, 山本雅之, 鈴木教郎, 三枝大輔, 三枝大輔

日本薬学会年会要旨集(Web)　144th　2024年

ISSN： 0918-9823
ニーマンピック病C型病態分子機構の解明に向けたモデル細胞によるプロテオーム変動解析

三好慶太郎, 前川正充, 前川正充, 前川正充, 菱沼英史, 菱沼英史, 松川直美, 小柴生造, 小柴生造, 深澤征義, 眞野成康, 眞野成康

日本薬学会年会要旨集(Web)　144th　2024年

ISSN： 0918-9823
大規模解析に向けた血漿プロテオミクス基盤の構築と卵巣がんバイオマーカー探索への応用

松川直美, 菱沼英史, 菱沼英史, 嶋喜子, 重田昌吾, 工藤敬, 島田宗昭, 島田宗昭, 島田宗昭, 小柴生造, 小柴生造

日本プロテオーム学会大会プログラム・抄録集　2024 (Web)　2024年
血漿メタボローム解析を用いた婦人科癌におけるバイオマーカーの探索

菱沼英史, 菱沼英史, 島田宗昭, 島田宗昭, 島田宗昭, 松川直美, 萩原達也, 工藤敬, 渋谷祐介, 重田昌吾, 元池育子, 元池育子, 徳永英樹, 徳永英樹, 木下賢吾, 木下賢吾, 木下賢吾, 小柴生造, 小柴生造, 八重樫伸生, 八重樫伸生, 八重樫伸生

日本婦人科腫瘍学会学術講演会プログラム・抄録集(Web)　66th　2024年
海馬周辺の脳容積値と関連する血中メタボロームの探索

佐藤和, 藤原和樹, 長尾健児, 今泉明, 小柴生造, 佐藤允治, 元池育子, 木下賢吾, 山本雅之

Dementia Japan　37　(4)　2023年

ISSN： 1342-646X
血中代謝プロファイルに遺伝・環境要因が与える影響の解析

小柴生造, 小柴生造, 元池育子, 元池育子, 菱沼英史, 菱沼英史, 青木裕一, 櫻井美由紀, 佐藤允治, 七谷圭, 七谷圭, 田高周, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

日本生化学会大会(Web)　96th　2023年
液体クロマトグラフィー/タンデム質量分析法を用いたニーマンピック病C型モデル細胞内プロテオーム変動解析

三好慶太郎, 前川正充, 前川正充, 前川正充, 菱沼英史, 菱沼英史, 松川直美, 小柴生造, 小柴生造, 深澤征義, 眞野成康, 眞野成康

次世代を担う若手のためのフィジカル・ファーマフォーラム講演要旨集　19th　2022年
ニーマンピック病C型モデル細胞内プロテオーム変動解析の基礎検討

三好慶太郎, 前川正充, 前川正充, 前川正充, 菱沼英史, 菱沼英史, 松川直美, 小柴生造, 小柴生造, 深澤征義, 眞野成康, 眞野成康

バイオメディカル分析科学シンポジウム講演要旨集　34th　2022年

ISSN： 1347-2364
メタボローム解析による糖尿病網膜症のバイオマーカーの探索

安田正幸, 國方彦志, 児玉慎二郎, 岡部達, 菱沼英史, 菱沼英史, 瀧澤廣輝, 片桐秀樹, 小柴生造, 小柴生造, 中澤徹, 中澤徹

日本眼科学会雑誌　126　2022年

ISSN： 0029-0203
新規に同定したガラクトース血症IV型における国内頻度と臨床像に関する研究

和田陽一, 菊池敦生, 岩澤伸哉, 市野井那津子, 小柴生造, 呉繁夫

日本小児科学会雑誌　125　(2)　203-203　2021年2月
出版者・発行元： (公社)日本小児科学会
ISSN： 0001-6543
代謝プロファイルに影響を与える遺伝要因の網羅的解析

小柴生造, 小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 井上仁, 菱沼英史, 青木裕一, 青木裕一, 田高周, 田高周, 城田松之, 城田松之, 城田松之, 木下賢吾, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之, 山本雅之

日本生化学会大会(Web)　94th　2021年
大規模コホート研究におけるGC-MS/MSハイスループット分析系の開発

松川直美, 菱沼英史, 三枝大輔, 小柴生造, 山本雅之

JSBMS Letters　46　(Supplement)　2021年

ISSN： 1881-5464
子宮体癌における血漿メタボローム解析によるバイオマーカーの探索

辻圭太, 島田宗昭, 菱沼英史, 重田昌吾, 李賓, 宮原周子, 土岐麻実, 工藤敬, 徳永英樹, 小柴生造, 木下賢吾, 山本雅之, 八重樫伸生

日本婦人科腫瘍学会雑誌　39　(1)　297-297　2021年1月
出版者・発行元： (公社)日本婦人科腫瘍学会
ISSN： 1347-8559
がん代謝を標的とした卵巣癌におけるバイオマーカーの探索

工藤敬, 島田宗昭, 菱沼英史, 重田昌吾, 李賓, 宮原周子, 土岐麻実, 辻圭太, 徳永英樹, 小柴生造, 木下賢吾, 山本雅之, 八重樫伸生

日本婦人科腫瘍学会雑誌　39　(1)　298-298　2021年1月
出版者・発行元： (公社)日本婦人科腫瘍学会
ISSN： 1347-8559
血漿メタボロームと頸動脈内膜中膜肥厚の関連

寳澤篤, 小柴生造, 平田匠, 中村智洋, 土屋菜歩, 成田暁, 小暮真奈, 元池育子, 三枝大輔, 峯岸直子, 栗山進一, 田宮元, 辻一郎, 木下賢吾, 呉繁夫

日本高血圧学会総会プログラム・抄録集　42回　304-304　2019年10月
出版者・発行元： (NPO)日本高血圧学会
コホート調査における代謝プロファイルの経時変化の解析

小柴生造, 元池育子, 三枝大輔, 井上仁, 菱沼英史, 青木裕一, 田高周, 城田松之, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　92回　[1T12a-04]　2019年9月
出版者・発行元： (公社)日本生化学会
【次世代に向けたアンチ・ドーピング】ドーピング分析の最前線日本アンチ・ドーピング研究コンソーシアムの挑戦

小柴生造, 山本雅之

体育の科学　69　(7)　504-509　2019年7月
出版者・発行元： (株)杏林書院
ISSN： 0039-8985
メタボロームデータを用いた非線形変数選択機械学習によるうつ状態の予測

高橋雄太, 植木優夫, 山田誠, 田宮元, 元池育子, 三枝大輔, 櫻井美由紀, 長神風二, 小柴生造, 木下賢吾, 山本雅之, 富田博秋

精神神経学雑誌　(2019特別号)　S609-S609　2019年6月
出版者・発行元： (公社)日本精神神経学会
ISSN： 0033-2658
GALMの両アレル性変異はガラクトース血症IV型を呈する(Blallelic GALM pathogenic variants cause a novel type of galactosemia)

和田陽一, 菊池敦生, 市野井那津子, 坂本修, 竹澤祐介, 岩澤伸哉, 新堀哲也, 入月浩美, 中島葉子, 小川えりか, 石毛美夏, 平井洋生, 笹井英雄, 藤木亮次, 伊藤哲也, 小原収, 青木洋子, 小柴生造, 深尾敏幸, 呉繁夫

日本小児科学会雑誌　123　(2)　280-280　2019年2月
出版者・発行元： (公社)日本小児科学会
ISSN： 0001-6543
GALMの両アレル性変異はガラクトース血症IV型を呈する(Blallelic GALM pathogenic variants cause a novel type of galactosemia)

和田陽一, 菊池敦生, 市野井那津子, 坂本修, 竹澤祐介, 岩澤伸哉, 新堀哲也, 入月浩美, 中島葉子, 小川えりか, 石毛美夏, 平井洋生, 笹井英雄, 藤木亮次, 伊藤哲也, 小原収, 青木洋子, 小柴生造, 深尾敏幸, 呉繁夫

日本小児科学会雑誌　123　(2)　280-280　2019年2月
出版者・発行元： (公社)日本小児科学会
ISSN： 0001-6543
次世代型プロテオミクスによる妊娠高血圧腎症の診断マーカーの同定

樋口友也, 内田康雄, 内田康雄, 加賀美智史, 城田松之, 城田松之, 三枝大輔, 三枝大輔, 小柴生造, 小柴生造, 栗山進一, 栗山進一, 菅原準一, 菅原準一, 寺崎哲也, 寺崎哲也

日本薬学会東北支部大会講演要旨集　58th　2019年
大規模コホート研究におけるGC-MS/MSによるヒト血漿メタボローム解析

三枝大輔, 三枝大輔, 松川直美, 松川直美, 田高周, 田高周, 元池育子, 元池育子, 小柴生造, 小柴生造

日本プロテオーム学会誌(Web)　4　(1)　2019年

ISSN： 2432-2776
Estimating frequency of pathogenic variants in a Japanese population by using the whole-genome reference panel of ToMMo

Yumi Yamaguchi-Kabata, Jun Yasuda, Osamu Tanabe, Yoichi Suzuki, Hiroshi Kawame, Nobuo Fuse, Masao Nagasaki, Yosuke Kawai, Kaname Kojima, Fumiki Katsuoka, Sakae Saito, Inaho Danjoh, Ikuko N. Motoike, Riu Yamashita, Seizo Koshiba, Daisuke Saigusa, Gen Tamiya, Shigeo Kure, Nobuo Yaegashi, Yoshio Kawaguchi, Fuji Nagami, Shinichi Kuriyama, Junichi Sugawara, Naoko Minegishi, Atsushi Hozawa, Soichi Ogishima, Hideyasu Kiyomoto, Takako Takai-Igarashi, Kengo Kinoshita, Masayuki Yamamoto

HUMAN GENOMICS　12　2018年3月

ISSN： 1473-9542

eISSN： 1479-7364
ゲノム情報と連携した日本人多層オミックス参照パネルの意義

小柴生造, 小柴生造, 元池育子, 元池育子, 三枝大輔, 三枝大輔, 井上仁, 井上仁, 城田松之, 城田松之, 青木裕一, 青木裕一, 田高周, 田高周, 斎藤智, 木下賢吾, 木下賢吾, 山本雅之, 山本雅之

糖尿病(Web)　61　(Suppl)　2018年

ISSN： 1881-588X
メタボローム解析による血液検体保管条件の検討

井上仁, 三枝大輔, 工藤久智, 峯岸直子, 峯岸直子, 小柴生造, 山本雅之, 山本雅之

日本生化学会大会(Web)　90th　ROMBUNNO.2P‐0981 (WEB ONLY)-0981]　2017年12月
出版者・発行元：生命科学系学会合同年次大会運営事務局
経口アルカリ性化剤により薬物的血液浄化される尿毒症物質の検討

阿部倫明, 三枝大輔, 小柴生造, 鈴木洋一, 田邉修, 安田純, 佐藤文俊, 工藤正孝, 佐藤博, 森本玲, 中道崇, 小川晋, 清元秀泰, 三木俊, 高山真, 宮崎真理子, 石井正, 伊藤貞嘉

日本腎臓学会誌　59　(3)　234-234　2017年4月25日
出版者・発行元： (一社)日本腎臓学会
ISSN： 0385-2385
質量分析計を用いる大規模メタボローム解析におけるデータ補正について

三枝大輔, 三枝大輔, 三枝大輔, 元池育子, 元池育子, 小柴生造, 小柴生造

質量分析総合討論会講演要旨集　65th　2017年
マルチオミクスが解き明かす疾患生物学日本人多層オミックス参照パネルの拡張

小柴生造, 三枝大輔, 元池育子, 小島要, 城田松之, 齋藤智, 勝岡史城, 河合洋介, 山口由美, 田邉修, 長崎正郎, 安田純, 木下賢吾, 山本雅之

日本生化学会大会プログラム・講演要旨集　89回　[1S05-5]　2016年9月
出版者・発行元： (公社)日本生化学会
19F標識技術を利用したKeap1-Nrf2タンパク質の構造機能解析

小柴生造, 小柴生造, 小柴生造, 渡部暁, 碇正臣, 碇正臣, 松田夏子, 松田夏子, 磯達朗, 鈴木隆史, 木川隆則, 木川隆則, 木川隆則, 山本雅之, 山本雅之

日本分子生物学会年会プログラム・要旨集(Web)　39th　2016年
大規模コホートにおけるトランスオミクス解析

三枝大輔, 三枝大輔, 三枝大輔, 元池育子, 元池育子, 小柴生造, 小柴生造

日本プロテオーム学会大会プログラム・抄録集　2016　2016年
日本人多層オミックス参照パネルの公開

小柴生造, 加藤恭丈, 三枝大輔, 元池育子, 城田松之, 斎藤智, 田邉修, 安田純, 木下賢吾, 山本雅之

日本生化学会大会(Web)　88th　4T21L-07(3P0816) (WEB ONLY)-07(3P0816)]　2015年12月
出版者・発行元： (公社)日本生化学会
LC‐MSによる大規模コホートメタボローム解析

三枝大輔, 加藤恭丈, 小柴生造, 元池育子, 荻島創一, 本橋ほづみ, 菅原準一, 中谷純, 寳澤篤, 峯岸直子, 木下賢吾, 田邉修, 山本雅之

日本農芸化学会大会講演要旨集(Web)　2015　4SY19-2 (WEB ONLY)　2015年3月5日

ISSN： 2186-7976
血漿プロテオームによる大規模住民コホート研究

加藤恭丈, 小柴生造, 五十嵐和彦, 山本雅之, 田邉修, 蝦名真行, 城田松之, 元池育子, 木下賢吾, 工藤久智, 信國宇洋, 峯岸直子, 三枝大輔

日本プロテオーム学会大会要旨集　2015　(0)　62-62　2015年
出版者・発行元：日本プロテオーム学会（日本ヒトプロテオーム機構）
DOI： 10.14889/jhupo.2015.0.62.0 　
ジャガイモ疫病菌が分泌するエフェクターAVR3aの病原性機能には脂質との結合が必要である

八丈野孝, LI H, CHAPARRO‐GARCIA Angela, SCHORNACK Sebastian, 小柴生造, 渡部暁, 木川隆則, KAMOUN Sophien, 白須賢

日本植物病理学会大会プログラム・講演要旨予稿集　2012　90　2012年3月15日
ジャガイモ疫病菌が分泌するRXLRエフェクターAVR3aの病原性機能にはホスファチジルイノシトールリン酸との結合が必要である

八丈野孝, 李華, CHAPARRO‐GARCIA Angela, SCHORNACK Sebastian, 小柴生造, 渡部暁, 木川隆則, KAMOUN Sophien, 白須賢

日本植物生理学会年会要旨集　53rd　149　2012年3月9日
ジャガイモ疫病菌エフェクターAVR3aの立体構造および機能解析

八丈野孝, 門田康弘, 瀧澤香, LI H, 大沢登, 半田徳子, 寺田貴帆, 小柴生造, 白水美香子, 渡部暁, 木川隆則, 横山茂之, KAMOUN Sophien, 白須賢

日本植物病理学会大会プログラム・講演要旨予稿集　2011　56　2011年3月11日
ジャガイモ疫病菌エフェクターAVR3aの構造機能解析

八丈野孝, 渡部暁, 木川隆則, 横山茂之, Kamoun Sophien, 白須賢, 門田康弘, 瀧澤香, 李華, 大沢登, 半田徳子, 寺田貴帆, 小柴生造, 白水美香子

日本植物生理学会年会およびシンポジウム講演要旨集　2011　(0)　294-294　2011年
出版者・発行元：日本植物生理学会
DOI： 10.14841/jspp.2011.0.0294.0 　

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病原菌は病原性タンパク質であるエフェクターを植物の細胞内に多数送り込み、PAMP (pathogen-associated molecular pattern)の認識シグナルにより誘導される防御反応を撹乱し抑制する。それに対して植物は抵抗性タンパク質（Rタンパク質）によってエフェクターを認識し、より強い防御反応を誘導する。ジャガイモ疫病菌(Phytophthora infestans)のエフェクターAVR3aは植物細胞内へ入り、PAMPであるINF1の認識シグナルを抑制するが、そのメカニズムはよくわかっていない。アミノ酸配列からはその機能を推測することができないため、タンパク質の立体構造解析を行った。その結果、AVR3aは4つのαヘリックスが束になった構造を持つことが明らかとなった。表面電荷分布を基に解析したところ、正電荷のアミノ酸が集中する特徴的な領域が膜脂質であるホスファチジルイノシトールリン酸の結合に重要であることがわかった。この領域に変異を持つAVR3aは、Rタンパク質であるR3aによって認識されるが、INF1の認識シグナルを抑制することができなかった。このことから、ホスファチジルイノシトールリン酸の結合がAVR3aの病原性の機能に重要な役割を持つことが示唆された。本発表では、AVR3aの立体構造から見えてきた脂質結合領域と病原性の機能との関係について議論する。
病原菌エフェクタータンパク質の立体構造解析

八丈野孝, 白水美香子, 横山茂之, 木川隆則, Kamoun Sophien, 白須賢, Li Hua, 門田康弘, 瀧澤香, 大沢登, 寺田貴帆, 半田徳子, 小柴生造, 渡部暁

日本植物生理学会年会およびシンポジウム講演要旨集　2010　(0)　81-81　2010年
出版者・発行元：日本植物生理学会
DOI： 10.14841/jspp.2010.0.0081.0 　

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病原菌はエフェクタータンパク質を植物の細胞内に多数注入し、抵抗性反応を撹乱し抑制する。それに対して、ある植物はエフェクターを認識し、より強い抵抗性反応を誘導し防御する。このような植物-病原菌相互作用に関与する遺伝子は数多く単離されているが、エフェクターとそれを認識する抵抗性タンパク質（Rタンパク質）の作用機作およびそのシグナル伝達様式はあまりわかっていない。特にエフェクターについてはアミノ酸配列からその機能を推測できないことが多く、抵抗性反応を抑制するメカニズムを解析することは困難である。そこで、エフェクターとRタンパク質の作用機作およびエフェクターの抵抗性抑制メカニズムを分子レベルで明らかにすることを目的として、タンパク質の立体構造解析を行った。立体構造解析にはタンパク質の可溶性が不可欠であるため、可溶化条件の改善が可能な無細胞タンパク質発現系をベースにしたハイスループット発現系を用いて、約260種類のエフェクターおよび抵抗性関連タンパク質をスクリーニングした。その結果、約90種のタンパク質が可溶性として得られた。さらに我々は、ジャガイモ疫病菌由来のエフェクターの立体構造解析に成功した。本発表では、このエフェクターの立体構造とそこから見えてきた機能について報告する。
Ubiquitin regulatory X(UBX) domain-containing(UBXD)タンパク質に含まれる非典型的Ubiquitin associated(UBA)ドメインの構造と機能

栃尾尚哉, 松田憲之, 松田憲之, ZHAO Chenhua, 小柴生造, 小柴生造, 原田拓志, 渡部暁, 井上真, 青木雅昭, 松田貴意, 関英子, 関英子, 鞆康子, 横山茂之, 横山茂之, 木川隆則, 木川隆則

生化学　2008年

ISSN： 0037-1017
human tripartite motifタンパク質ファミリーのRINGドメインの溶液構造

宮本和英, 木川隆則, 木川隆則, 栃尾尚哉, 佐藤真奈美, 苫米地由里, 小柴生造, 井上真, 横山茂之, 横山茂之

Abstracts. Annual Meeting of the NMR Society of Japan　45th　2006年
NMRによる網羅的構造解析はプレクストリン相同ドメインの多様な世界を示す

LI Hua, NAKANISHI Tamiji, SATO Manami, SUETAKE Tetsuya, YONEYAMA Misao, TOMIZAWA Tadashi, TOCHIO Naoya, SAITO Kohei, HAYASHI Fumiaki, NEMOTO Nobuaki, IZUMI Kenya, HARADA Takushi, INOUE Makoto, KOSHIBA Seizo, TERADA Takaho, TANAKA Akiko, SUGANO Sumio, HAYASHIZAKI Yoshihide, OHARA Osamu, OHARA Osamu, KIGAWA Takanori, KIGAWA Takanori, YOKOYAMA Shigeyuki, YOKOYAMA Shigeyuki

Abstracts. Annual Meeting of the NMR Society of Japan　45th　2006年
3P066 ホメオタンパク質に含まれる共通ドメインホメオボックスの分類と代表構造の決定(蛋白質 C) 物性 : 安定性、折れたたみなど)

鎌足雄司, 近山英輔, 小柴生造, 林文晶, 廣田洋, 好田真由美, 井上真, 矢吹孝, 青木雅昭, 関英子, 寺田貴帆, 斉藤講平, 白水美香子, 田仲昭子, 小原収, 菅野純夫, 関原明, 篠崎一雄, 林崎良英, 川井悟, 木川隆則, 横山茂之, 泉顕也, Tomo Y, 金野大助, 中村安里, 阿部孝政, 清宮恭子, 葛西卓磨, 栃尾尚哉

生物物理　44　(0)　2004年
出版者・発行元：一般社団法人日本生物物理学会
ISSN： 0582-4052
ICADのC末端ドメインのNMRによる構造解析

福島径, 黒田裕, 菊地淳, 小柴生造, 横山茂之

NMR討論会講演要旨集　40th　348-349　2001年11月1日
PHドメインやそれ以外のシグナル伝達ドメインの構造生物学 (構造生物学のフロンティア--シグナル伝達とDNAトランスアクション) -- (細胞内シグナル伝達)

小柴生造, 横山茂之

蛋白質核酸酵素　44　(4)　368-379　1999年3月
出版者・発行元：共立出版
ISSN： 0039-9450

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共同研究・競争的資金等の研究課題 9

病態に強固な関連がある敗血症新規サブクラス分類の開発

工藤大介, 田宮元, 早川峰司, 菱沼英史, 久志本成樹, 成田暁, 山川一馬, 佐藤哲哉, 小柴生造, 湯本哲也, 後藤匡啓, 近藤豊, 石原唯史, 佐藤幸男, 錦見満曉, 堤悠介, 高山渉, 鈴木浩大, 春日井大介

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2024年4月1日～ 2026年3月31日
病態に強固な関連がある敗血症新規サブクラス分類の開発

工藤大介, 田宮元, 早川峰司, 菱沼英史, 久志本成樹, 成田暁, 山川一馬, 佐藤哲哉, 小柴生造, 後藤匡啓

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Tohoku University

2023年4月1日～ 2026年3月31日
左室駆出率が保持された心不全に対する個別化医療を目指した多分野融合研究

安斉俊久, 永井利幸, 小川貴弘, 横田勲, 清水厚志, 平田健司, 小柴生造, 櫻井美佳

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (B)

研究機関：Hokkaido University

2020年4月1日～ 2024年3月31日

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HFpEF計500症例を目標に以下の組み入れ基準・除外基準で北海道大学病院を含む全国24施設からElectronic Data Captureシステムを用いて詳細な臨床情報を含めて登録し、各種解析を並行して実施した。組み入れ基準：外来もしくは入院心不全症例：①20歳以上でフラミンガム心不全診断基準を満足する心不全症状/所見があり、②左室駆出率50％以上かつBNP値100pg/mLを超えるもしくはN末端proBNP値400 pg/mLを超える、③本人からの文書同意が可能。除外基準：①敗血症、②心筋炎、③閉塞型肥大型心筋症、④拘束型心筋症、⑤重度の弁膜症、⑥心臓移植後あるいは待機、⑦1か月以内の予定心臓手術各種解析：①心不全マルチバイオマーカー解析 ②アレイ（ゲノムワイド関連）解析 ③網羅的メタボローム解析 ④人工知能解析今年度は昨年度に引き続き、上記基準に該当する心不全症例の登録を開始してきた。令和4年3月末の時点で、目標症例数を超えるHFpEF664例の登録が得られ、バイオマーカー、アレイ、メタボローム解析も完了した。また、歩行動画の統一条件撮影に関しては昨年度特許申請に至った撮影アプリケーションを用いて現在歩行動画が回収できた192例に対し、歩行パターンの機械学習によるクラスター解析を行っており、教師なし学習で臨床医が判定した臨床フレイルスケールを高い弁別能で予測出来ることに加え、予後との関連も明らかになりつつある。
乳癌罹患リスク低減に向けた遺伝子多型、生活習慣、血漿メタボロームの統合解析

石田孝宣, 寳澤篤, 布施昇男, 濱中洋平, 小柴生造, 栗山進一

2020年4月1日～ 2023年3月31日

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乳癌死亡数を減らすためには、個々の女性の乳癌罹患リスクを的確に評価し、そのリスクを低減することは重要な課題である。本研究は、日本人女性が自分の遺伝子多型と血漿メタボローム情報をもとに、乳癌罹患リスクを低減するために生活習慣をどのように改善すればよいかを知り、その効果を血漿メタボローム変化で知る個別化予防の構築を目的とする。本研究はToMMoおよび大学病院のバイオバンクを利活用して、一般住民と乳癌患者の遺伝子多型、生活習慣、血漿メタボロームのデータを用いて解析する。乳癌罹患リスクに関連のある84の遺伝子多型、8つの血漿代謝物、改善・変更可能な身体情報・生活習慣（食習慣、住環境、睡眠、運動、嗜好、内服薬など）、および乳癌罹患の情報を用いて解析を行う。コホート参加者の生活調査は登録時に行われており、全コホート参加者の全ゲノムシークエンスもしくはアレイ解析によるゲノム解析、血漿メタボローム解析が進められている。メタボローム解析は、NMR、GC-MS、LC-MSの3法が用いられおり、標的メタボローム解析法のMXp Quant 500 Kitを用いたLC-MS解析（500代謝物）は1,000人以上の成人女性に行われる予定である。東北大学病院に通院している乳癌既往者約1,700人のうち、乳癌術後の無再発患者は約1,300人である。2021年度末には、計約800人が登録して血液検体保存がされる見込みであり、2022年度以降に、ToMMoが開発したSNPアレイであるジャポニカアレイNEOを用いたゲノム解析およびMXp Quant 500 Kitを用いたLC-MS解析を行う計画である。以上の全体の研究実施計画のうち、2021年度は、大学病院においては乳癌患者のバイオバンク登録をすすめるとともに、メタボローム解析を行うためのデータ整理を行った。
１９F-NMR法と常磁性効果を用いた細胞内環境下のタンパク質の基質認識機構の解明

小柴生造

2017年4月1日～ 2023年3月31日

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本研究では、申請者がこれまで開発してきた各種19F標識技術、In-Cell NMR法、および常磁性効果による構造解析法を組み合わせて、細胞内におけるタンパク質の様々な分子認識機構を解析し、本来タンパク質が機能しているin vivo環境下での動的構造変化を解明することを目的とする。本研究の令和３年度の成果は以下の通りである。昨年度までに実施した、酸化ストレス応答タンパク質Keap1と基質である転写因子Nrf2の相互作用の解析の成果は論文として公開された（Commun. Biol. 4,576, 2021)。一方、Keap1のもう一つの基質である各種親電子性物質（化合物）とKeap1の相互作用について、引き続き各種NMR法を用いて詳細な解析を実施した。さらに令和3年に東北大学に新たに導入された最新鋭の300kVクライオ電子顕微鏡を活用して、Keap1とNrf2の複合体の立体構造解析を実施し、従来と比較して大きく分解能が向上した構造を得ることに成功した。今後は引き続き解析を進めて複合体の構造の詳細を解明すると共に、In-Cell NMR法と組み合わせることでKeap1の様々な分子認識による構造変化を明らかにする。一方、令和2年度に引き続きドメイン間の構造変化の解析のために、マルチドメインタンパク質である各種代謝酵素（PAH,ASPG等）についても解析を進めている。特にPAHに関してはクライオ電子顕微鏡による解析を実施し、こちらも従来と比較して大きく分解能が向上した構造を得ることに成功した。今後は最終的な目標である細胞内環境下における分子認識機構の解析法の確立に向けて、これまで解析したKeap1等のタンパク質について細胞内に高効率に導入し、ドメイン間の構造変化を各種19F-NMR法や常磁性効果を組み合わせることにより解析を進める。
食事・栄養素が認知指標および脳形態に与える影響の解明－オミックス解析を用いた検討

小暮真奈, 瀧靖之, 寳澤篤, 小柴生造

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2017年4月1日～ 2021年3月31日

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食事・食品摂取と脳形態との関連を検討した結果、エネルギー摂取量が未調整であるものの、きのこ類の摂取量は他の調整項目と独立して灰白質容量と有意な正の関連が認められた。また、食事パターンでみると、洋食パターンスコアが中央値以上のグループで有意に灰白質容量および海馬左右平均容量が多かった。さらに、上記の分析モデルにオミックス解析結果を加えて検討した結果、アミノ酸が両者の関連を修飾している可能性が示唆された。今回、オミックス解析結果については代表的なアミノ酸のみの結果を用いて検討したが、今後も共同研究等で詳細に検討し、脳の健康に寄与しうる代謝物質について明らかにする予定である。
慢性腎臓病における代謝性アシドーシスの治療介入がもたらす腎保護機序の解明

阿部倫明, 小柴生造, 三枝大輔, 庄子睦美

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2016年4月1日～ 2019年3月31日

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本研究における主な発見を以下に記す。１．アルカリ性化剤介入前後における血漿および尿のLC-MS/MSによる尿毒症物質の定量的メタボローム解析の結果、クエン酸Na・K投与群でインドキシル硫酸・パラクレジル硫酸・アルギニノコハク酸の尿中排泄が増加し、インドキシル硫酸の血中濃度が低下した。２．クエン塩Na・K投与によって酸性尿の改善が認められたが、特に早朝尿に比べ随時尿のpH改善が大きいほど腎機能は良い傾向が認められた。クエン酸Na・Kは重曹とは異なりアルカリ性化以外の腎保護効果が期待できる可能性が示唆された。今後の慢性腎臓病の新規治療戦略の骨幹となる可能性が考えられた。
１９F-NMR法を用いた細胞内環境下におけるタンパク質の動的構造の解明

小柴生造

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Scientific Research (C)

研究機関：Tohoku University

2014年4月1日～ 2018年3月31日

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人の体の中で様々な機能を果たすタンパク質はそれぞれ特徴的な立体構造を持っており、機能に際して構造が変化することが知られている。しかし従来の研究では単離したタンパク質を試験管内で解析しており、細胞内のように多種類の分子が存在する環境下でのタンパク質の構造変化を調べる研究は技術的に難しかった。本研究では、細胞内においてタンパク質を特異的に且つ高感度に測定できるフッ素をタンパク質に導入し、核磁気共鳴法で測定するための実験系を確立した。またこの方法を活用してタンパク質と基質との相互作用を観測することにも成功した。本成果は今後のタンパク質科学や細胞生物学の発展に大きく貢献するものである。
Ｉｎ－ＣｅｌｌＮＭＲ法を用いたＶＲＫ１キナーゼタンパク質の動的構造の解明

小柴生造

提供機関：Japan Society for the Promotion of Science

制度名：Grants-in-Aid for Scientific Research

研究種目：Grant-in-Aid for Young Scientists (B)

2012年4月1日～ 2015年3月31日

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本研究では，細胞内における特定のタンパク質のふるまいを，核磁気共鳴（NMR）法とフッ素（１９Ｆ）標識法を組み合わせて選択的に観測するための技術を開発した．またこの技術を用いて生体内で重要な役割を果たしているタンパク質の細胞内におけるNMR信号の観測に成功した．これは，これまで試験管内で解析されてきたタンパク質の構造変化を，実際に機能している生きた細胞内環境下で解明するために必要な重要な技術である．

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