研究者詳細

顔写真

サトウ　コウタ
佐藤　孝太
Kota Sato
所属
大学院医学系研究科　視覚先端医療学寄附講座
職名
助教
学位

  • 学術博士

e-Rad 研究者番号
50732327

研究分野 1

  • ライフサイエンス / 眼科学 /

論文 74

  1. AAV2-driven endothelin induces chronic reduced retinal blood flow/retinal ganglion cell loss in rats. 国際誌

    Ge Shi, Kota Sato, Nana Takahashi, Michiko Ohno-Ohishi, Namie Murayama, Chiaki Yamaguchi, Daisuke Saigusa, Toru Nakazawa

    Life science alliance　8　(8)　2025年8月

    DOI： 10.26508/lsa.202403087 　

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    Dysfunction of ocular blood flow (BF) is believed to be one of the causes of glaucomatous pathology. However, whether this dysfunction is indeed a cause or is actually a consequence of optic nerve degeneration remains controversial. Here, we established a new animal model of chronic BF reduction in the retina to mimic glaucoma. We found that retinal BF in rats, as measured with laser speckle flowgraphy, was significantly reduced 3 wk after an intravitreal injection of AAV2-human endothelin-1 (AAV2-hEDN1). The number of retinal ganglion cells was also reduced in rats that received AAV2-hEDN1 injection. Immunostaining signals for GFAP and the endothelin-B receptor were enhanced in the rat retinas after AAV2-hEDN1 injection. Moreover, mRNA levels of Ripk1/Ripk3 and Tnf in the retina increased, and glutathione levels in the aqueous humor decreased in rats that received AAV2-hEDN1 injection. Our findings demonstrate that endothelin-induced chronic retinal BF reduction leads to increased astrocyte activation and oxidative stress, which in turn induces retinal ganglion cell necroptosis. This suggests that methods to improve ocular BF have potential as novel therapies for glaucoma.

  2. Reduced plasma oxytocin levels in patients with open-angle glaucoma.

    Yurina Yamada, Kota Sato, Satoru Tsuda, Yu Yokoyama, Noriko Himori, Naoki Kiyota, Naoki Takahashi, Yoko Takeda, Chiaki Yamaguchi, Kazuko Omodaka, Toru Nakazawa

    Japanese journal of ophthalmology　2025年7月14日

    DOI： 10.1007/s10384-025-01248-6 　

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    PURPOSE: We explored the role of oxytocin in glaucoma by measuring the blood levels of oxytocin in glaucoma patients, comparing them to normal control subjects, and examining its association with clinical parameters. STUDY DESIGN: Retrospective cross-sectional study. MATERIAL AND METHODS: After obtaining informed consent from 181 glaucoma patients and 44 age-matched control participants, we collected blood samples in ethylenediaminetetraacetic acid (EDTA) tubes and centrifuged them at 2000 g for 25 minutes at 4 °C. The resulting plasma was assayed for oxytocin concentration with an Enzyme Linked Immunosorbent Assay (ELISA) kit. We compared oxytocin concentrations in the control and glaucoma groups, and within the glaucoma group, we determined whether the oxytocin levels were correlated with mean deviation (MD) and sectoral total deviation (TD). Furthermore, in 33 patients who underwent at least five visual field tests over a two-year period following oxytocin measurements and received no surgical interventions during that time, we determined whether the oxytocin levels were correlated with MD slope and sectoral TD slopes. RESULTS: Oxytocin levels in glaucoma patients were significantly lower than in age- and sex-matched normal controls (723.34 ± 303.44 vs. 557.59 ± 296.04 pg/ml, p=0.002). In glaucoma patients, oxytocin levels were significantly correlated with MD and inferior TD after adjustment for age and sex (β=0.149, p=0.041; β=0.156, p=0.034, respectively). There was a weak negative correlation between oxytocin concentration and MD slope (β=-0.334, p=0.084) and a weak negative correlation with central TD slope (β=-0.405, p=0.039), adjusted for age, sex, and history of additional eye drops. CONCLUSION: Oxytocin concentrations in glaucoma patients were significantly lower than in normal subjects and associated with the severity and progression of visual field defects. Given the wide variety of the pharmacological actions of oxytocin, it may be involved in the pathogenesis of glaucoma. Our results suggest that plasma oxytocin measurements may open a new avenue for glaucoma care.

  3. ENO1 Dysfunction-Mediated Glycolytic Attenuation Exacerbates Oxidative Stress-Induced Retinal Ganglion Cell Death via Altered ATP Synthesis Pathway. 国際誌

    Naoki Takahashi, Hiroshi Tawarayama, Yuri Chida, Minami Takeda, Risa Shiokawa, Kota Sato, Satoru Tsuda, Toru Nakazawa

    Investigative ophthalmology & visual science　66　(9)　63-63　2025年7月1日

    DOI： 10.1167/iovs.66.9.63 　

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    PURPOSE: The effects of enolase dysfunction-mediated glycolytic attenuation on oxidative stress-induced retinal ganglion cell (RGC) death were investigated. METHODS: Retinal expression of Enolase (ENO) 1 and 2 was detected using immunohistochemistry. Exogenous genes were introduced into mouse RGCs using viral vectors, and into the rat-derived retinal progenitor cell line R28 using lipofection. The effects of enolase dysfunction were evaluated using N-methyl-D-aspartate (NMDA)-induced RGC death and H2O2-induced death assays. Cell viability and gene expression were investigated using the alamarBlue, quantitative RT-PCR, and Western blotting, respectively. Reactive oxygen species (ROS) were detected using CM-H2DCFDA dye. 2-deoxyglucose and oligomycin were used to attenuate adenosine triphosphate (ATP) production in glycolysis and oxidative phosphorylation (OXPHOS), respectively. RESULTS: ENO1 and ENO2 were expressed in the RGCs. Enolase overexpression inhibited NMDA-induced mouse RGC death, whereas deficiency of ENO1 but not ENO2 enhanced cell death. Additionally, ENO1 overexpression prevented the CDKN2B-induced enhancement of RGC death. H2O2 treatment increased ENO1 expression in R28 cells and inhibited H2O2-induced cell death. ATP production was immediately enhanced in ENO1 wild-type cells treated with H2O2. 2-deoxyglucose and oligomycin prevented enhanced ATP production, but ATP levels were still higher than, or similar to, those in untreated wild-type cells; in contrast, in knockdown cells, oligomycin-mediated OXPHOS inhibition led to lower ATP production in H2O2-treatment than in untreated cells. H2O2 treatment increased ROS production in knockdown R28 cells. CONCLUSIONS: ENO1 dysfunction leads to glycolytic attenuation, resulting in an excessive dependence of ATP production on OXPHOS under oxidative stress, contributing to excitotoxicity-induced RGC death. Preventing glycolytic attenuation may represent a promising treatment for RGC degeneration.

  4. Risk Score Predicting Primary Open-Angle Glaucoma Patients With Vascular Predisposition. 国際誌

    Nana Takahashi, Yukihiro Shiga, Naoki Kiyota, Masayuki Yasuda, Naoki Takahashi, Kota Sato, Ryutaro Arita, Akiko Kikuchi, Shin Takayama, Tadashi Ishii, Toru Nakazawa

    Translational vision science & technology　14　(4)　9-9　2025年4月1日

    DOI： 10.1167/tvst.14.4.9 　

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    PURPOSE: We tested the hypothesis that a questionnaire-based risk score predicts the prevalence of patients with primary open-angle glaucoma (POAG) with vascular predisposition. METHODS: The Flammer Syndrome Questionnaire (FSQ) was used to determine vascular risk scores in 823 healthy subjects and 512 patients with POAG. Next, we characterized blood flow pulsatility changes within the optic nerve head (ONH) in Flammer syndrome (FS) using laser speckle flowgraphy (LSFG) in 358 eyes of 206 patients with normal-tension glaucoma (NTG). Last, we examined the association between changes in Mean blur rate (MBRAve), an LSFG-derived ONH blood flow measurement, during cold provocation and the FSQ risk score in 56 eyes of 56 patients with NTG. RESULTS: Five FSQ-related symptoms were significantly associated in patients with POAG patients; cold hands/feet (odds ratio [OR] = 1.82), low blood pressure (BP; OR = 3.29), increased response to drugs (OR = 2.27), underweight (OR = 1.99), and tendency toward perfectionism (OR = 1.88). The vascular risk score showed the best discriminative accuracy in differentiating healthy subjects from patients with NTG (area under the curve [AUC] = 0.73). In the NTG eyes, ONH pulsatile blood flow in the FS group was characterized by greater pulsatility. Moreover, the negative correlation between the high FSQ risk score and the cold-induced ONH blood flow reduction was pronounced in eyes with NTG (correlation coefficient = -0.41). CONCLUSIONS: The FSQ risk score can be a screening tool to identify patients with POAG with increased vascular stiffness and further reduced ONH blood flow during cold stress. TRANSLATIONAL RELEVANCE: The vascular risk score may help tailor individual glaucoma care.

  5. Proteome-Wide Analysis of Autoantibodies in Open-Angle Glaucoma in Japanese Population: A Pilot Study. 国際誌

    Naoko Takada, Makoto Ishikawa, Kota Sato, Hiroshi Kunikata, Takahiro Ninomiya, Akiko Hanyuda, Eriko Fukuda, Kei Yamaguchi, Chihiro Ono, Tomoko Kirihara, Chie Shintani, Chihiro Tsusu, Aki Osanai, Naoki Goshima, Yukitoshi Izumi, Charles F Zorumski, Toru Nakazawa

    Biomedicines　13　(3)　2025年3月14日

    DOI： 10.3390/biomedicines13030718 　

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    Objectives: The objective of this study was to identify novel autoantibodies specific for open-angle glaucoma (OAG), including normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG), using proteome-wide autoantibody screening and to determine their utility for diagnosis. Methods: We conducted proteome-wide autoantibody screening by wet protein arrays. Autoantibody reactivity in the plasma of OAG patients (50 NTG and 69 POAG patients) was quantitatively analyzed and compared to that of controls (35 cataract patients). The area under the curve (AUC) of the receiver operating characteristic (ROC) and multivariate analyses were used to determine diagnostic potential in patients with OAG. Results: Based on differences in autoantibody titers and positivity rates, four autoantibodies against ETNK1, VMAC, NEXN, and SUN1 were selected as potential biomarkers to discriminate OAG and cataract. In discrimination between POAG and cataract, the AUCs of ETNK1 and VMAC were calculated to be 0.820 (95%CI: 0.733-0.907) and 0.889 (95%CI: 0.818-0.959), respectively. Furthermore, the combination of these four antibodies demonstrated diagnostic potential for OAG with an AUC of 0.828 (95%CI: 0.757-0.898) by multivariate analysis. Conclusions: Four new glaucoma-associated autoantibodies were identified in this study. The differences in autoantibody patterns in the plasma between glaucoma and cataract patients support their potential utility as biomarkers for glaucoma screening.

  6. Precise Generation of Human Induced Pluripotent Stem Cell–derived Cell Lines Harboring Disease-relevant Single Nucleotide Variants Using a Prime Editing System

    Seiya Kanno, Kota Sato, Toru Nakazawa

    Bio-protocol　15　(4)　2025年2月20日

    DOI： 10.21769/BioProtoc.5191 　

    eISSN：2331-8325

  7. Precise Generation of Human Induced Pluripotent Stem Cell-derived Cell Lines Harboring Disease-relevant Single Nucleotide Variants Using a Prime Editing System

    Seiya Kanno, Kota Sato, Toru Nakazawa

    BIO-PROTOCOL　15　(4)　2025年2月20日

    DOI： 10.21769/BioProtoc.5191 　

    eISSN：2331-8325

  8. 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.

  9. Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals. 国際誌

    Masato Akiyama, Gen Tamiya, Kohta Fujiwara, Yukihiro Shiga, Yu Yokoyama, Kazuki Hashimoto, Masataka Sato, Kota Sato, Akira Narita, Sawako Hashimoto, Emi Ueda, Yoshihiko Furuta, Jun Hata, Masahiro Miyake, Hanako O Ikeda, Kenji Suda, Shogo Numa, Yuki Mori, Kazuya Morino, Yusuke Murakami, Sakurako Shimokawa, Shun Nakamura, Nobuyo Yawata, Kimihiko Fujisawa, Satoshi Yamana, Kenichiro Mori, Yasuhiro Ikeda, Kazunori Miyata, Keisuke Mori, Ken Ogino, Yoshito Koyanagi, Yoichiro Kamatani, Toshiharu Ninomiya, Koh-Hei Sonoda, Toru Nakazawa

    Ophthalmology　2024年7月17日

    DOI： 10.1016/j.ophtha.2024.05.026 　

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    PURPOSE: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. DESIGN: Cross-sectional analysis. PARTICIPANTS: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). METHODS: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. MAIN OUTCOME MEASURE: Proportion of patients with POAG after stratification according to the GRS. RESULTS: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35-8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79-9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10-4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10-6). CONCLUSIONS: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

  10. SH-SY5Y human neuronal cells with mutations of the CDKN2B-AS1 gene are vulnerable under cultured conditions

    Michiko Ohno-Oishi, Zou Meiai, Kota Sato, Seiya Kanno, Chihiro Kawano, Makoto Ishikawa, Toru Nakazawa

    Biochemistry and Biophysics Reports　38　2024年7月

    DOI： 10.1016/j.bbrep.2024.101723 　

    eISSN：2405-5808

  11. The relationship between equol production status and normal tension glaucoma. 国際誌

    Noriko Himori, Keiko Uchida, Takahiro Ninomiya, Masashi Nagai, Kota Sato, Satoru Tsuda, Kazuko Omodaka, Toru Nakazawa

    International ophthalmology　44　(1)　287-287　2024年6月27日

    DOI： 10.1007/s10792-024-03225-3 　

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    PURPOSE: Equol is metabolized by intestinal bacteria from soy isoflavones and is chemically similar to estrogen. Dietary habits, such as consumption of soy products, influence equol production. A relationship between glaucoma and estrogen has been identified; here, we investigated the relationship between equol production status and glaucoma in Japan. METHODS: We recruited 68 normal-tension glaucoma (NTG) patients (male to female ratio 26:42, average age 63.0 ± 7.6 years) and 31 controls (male to female ratio 13:18, average age 66.0 ± 6.3 years) from our hospital. All women included were postmenopausal. Urinary equol concentration was quantified with the ELISA method. MD was calculated based on the Humphrey visual field. The association between MD and equol was analyzed with Spearman's rank correlation coefficient. The Mann-Whitney U test was used to compare the equol-producing (> 1 μM) and non-producing (< 1 μM) subjects. We also investigated the association between equol and glaucoma with a logistic regression analysis. RESULTS: There was a significant association between equol and MD (r = 0.36, P < 0.01) in the NTG patients. Glaucoma, represented by MD, was significantly milder in the equol-producing subjects than the non-equol producing subjects (P = 0.03). A multivariate analysis revealed the independent contributions of equol, cpRNFLT, and IOP to MD (P = 0.03, P = 0.04, and P < 0.01, respectively). CONCLUSION: Our results suggest that equol, acting through estrogen receptor-mediated neuroprotective effects, might be involved in suppressing the progression of NTG. This result also adds to evidence that glaucoma may be influenced by lifestyle.

  12. Uric acid-driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation. 国際誌

    Hong Liang Lin, Sheng Wang, Kota Sato, Yu Qiao Zhang, Bei Ting He, Jing Xu, Toru Nakazawa, Yong Jie Qin, Hong Yang Zhang

    Cell death discovery　10　(1)　126-126　2024年3月9日

    DOI： 10.1038/s41420-024-01900-z 　

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    Excessive uric acid (UA) is associated with age-related cataract. A previous study showed that a high UA level in the aqueous humor stimulated the senescence of lens epithelial cells (LECs), leading to cataract progression. To better understand the underlying mechanisms, we investigated UA-driven senescence in human lens tissue samples obtained during surgery, rat lens organ cultures, and in vivo experiments, using senescence-associated β-galactosidase (SA-β-gal) staining, electronic microscopy, Western blotting, and histological analyses. Initially, we identified markedly higher expressions of NLRP3 and caspase-1 in the lens capsules of hyper-uricemic patients compared to normo-uricemic patients. This increase was accompanied by a significant rise in the SA-β-gal positive rate. We next built a cataract model in which rat lenses in an organ culture system were treated with an increasing dosage of UA. Notably, opacification was apparent in the lenses treated with 800 μM of UA starting on the fifth day. Mechanistically, UA treatment not only significantly induced the expression of NLRP3, caspase-1, and IL-1β, but also upregulated the levels of SA-β-gal and the senescence regulators p53 and p21. These effects were fully reversed, and lens opacification was ameliorated by the addition of MCC950, a selective NLRP3 antagonist. Moreover, an in vivo model showed that intravitreal UA injection rapidly induced cataract phenotypes within 21 days, an effect significantly mitigated by co-injection with MCC950. Together, our findings suggest that targeting the UA-induced NLRP3 inflammasome with MCC950 could be a promising strategy for preventing cataract formation associated with inflammageing.

  13. Author Correction: Reduced glutathione level in the aqueous humor of patients with primary open-angle glaucoma and normal-tension glaucoma. 国際誌

    Kota Sato, Daisuke Saigusa, Taiki Kokubun, Amane Fujioka, Qiwei Feng, Ritsumi Saito, Akira Uruno, Naomi Matsukawa, Michiko Ohno-Oishi, Hiroshi Kunikata, Yu Yokoyama, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Satoru Tsuda, Shigeto Maekawa, Masayuki Yamamoto, Toru Nakazawa

    npj aging　10　(1)　8-8　2024年1月20日

    DOI： 10.1038/s41514-024-00137-5 　

  14. New Dihydropyridine Derivative Attenuates NF-κB Activation via Suppression of Calcium Influx in a Mouse BV-2 Microglial Cell Line

    Kota Sato, Yuto Sasaki, Michiko Ohno-Oishi, Kuniyuki Kano, Junken Aoki, Kosuke Ohsawa, Takayuki Doi, Hiroyuki Yamakoshi, Yoshiharu Iwabuchi, Chihiro Kawano, Yoshiyuki Hirata, Toru Nakazawa

    The Tohoku Journal of Experimental Medicine　2024年

    出版者・発行元： Tohoku University Medical Press

    DOI： 10.1620/tjem.2024.j024 　

    ISSN：0040-8727

    eISSN：1349-3329

  15. Identification of OPTN p.(Asn51Thr): A novel pathogenic variant in primary open-angle glaucoma

    Yukihiro Shiga, Kazuki Hashimoto, Kosuke Fujita, Shigeto Maekawa, Kota Sato, Shintaroh Kubo, Kazuhide Kawase, Kana Tokumo, Yoshiaki Kiuchi, Sotaro Mori, Makoto Nakamura, Takeshi Iwata, Koji M. Nishiguchi, Toru Nakazawa

    Genetics in Medicine Open　2　100839-100839　2024年

    出版者・発行元： Elsevier BV

    DOI： 10.1016/j.gimo.2023.100839 　

    ISSN：2949-7744

  16. A ginger extract improves ocular blood flow in rats with endothelin-induced retinal blood flow dysfunction. 国際誌

    Nana Takahashi, Kota Sato, Naoki Kiyota, Satoru Tsuda, Namie Murayama, Toru Nakazawa

    Scientific reports　13　(1)　22715-22715　2023年12月20日

    DOI： 10.1038/s41598-023-49598-w 　

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    The aim of this study was to investigate the effect of a ginger extract on optic nerve head blood flow (ONH BF) under endothelin-1 (ET-1) stimulation. Using laser speckle flowgraphy, we measured ONH BF in brown Norway rats. To establish the ONH BF impairment profile under ET-1 stimulation, we administered an intravitreal injection of ET-1 under anesthesia. We then gave the ginger extract sublingually to assess its effect on ONH BF in both normal and ET-1-induced ischemic conditions. Post ET-1 injection, there were no significant changes in parameters including intraocular pressure or systemic factors. ONH BF showed a dose-dependent decline after ET-1 injection, with a significant reduction after a 2.50 pmol ET-1 dose. Sublingual administration of the ginger extract significantly improved ONH BF in both normal and ET-1-stimulated rats. This suggests that our newly developed supplement for improving ONH BF has a potential role in retinal ischemic diseases, including glaucoma.

  17. Reduced glutathione level in the aqueous humor of patients with primary open-angle glaucoma and normal-tension glaucoma. 国際誌

    Kota Sato, Daisuke Saigusa, Taiki Kokubun, Amane Fujioka, Qiwei Feng, Ritsumi Saito, Akira Uruno, Naomi Matsukawa, Michiko Ohno-Oishi, Hiroshi Kunikata, Yu Yokoyama, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Satoru Tsuda, Shigeto Maekawa, Masayuki Yamamoto, Toru Nakazawa

    npj aging　9　(1)　28-28　2023年11月21日

    DOI： 10.1038/s41514-023-00124-2 　

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    Glaucoma is a leading cause of blindness worldwide in older people. Profiling the aqueous humor, including the metabolites it contains, is useful to understand physiological and pathological conditions in the eye. In the current study, we used mass spectrometry (MS) to characterize the aqueous humor metabolomic profile and biological features of patients with glaucoma. Aqueous humor samples were collected during trabeculectomy surgery or cataract surgery and analyzed with global metabolomics. We included 40 patients with glaucoma (32 with POAG, 8 with NTG) and 37 control subjects in a discovery study. VIP analysis revealed five metabolites that were elevated and three metabolites that were reduced in the glaucoma patients. The identified metabolomic profile had an area under the receiver operating characteristic curve of 0.953. Among eight selected metabolites, the glutathione level was significantly decreased in association with visual field defects. Moreover, in a validation study to confirm the reproducibility of our findings, the glutathione level was reduced in NTG and POAG patients compared with a cataract control group. Our findings demonstrate that aqueous humor profiling can help to diagnose glaucoma and that various aqueous humor metabolites are correlated with clinical parameters in glaucoma patients. In addition, glutathione is clearly reduced in the aqueous humor of glaucoma patients with both IOP-dependent and IOP-independent disease subtypes. These findings indicate that antioxidant agents in the aqueous humor reflect glaucomatous optic nerve damage and that excessive oxidative stress may be involved in the pathogenesis of glaucoma.

  18. The GPR84 molecule is a mediator of a subpopulation of retinal microglia that promote TNF/IL-1α expression via the rho-ROCK pathway after optic nerve injury

    Kota Sato, Michiko Ohno-Oishi, Masaaki Yoshida, Taimu Sato, Takaharu Aizawa, Yuto Sasaki, Shigeto Maekawa, Makoto Ishikawa, Kazuko Omodaka, Chihiro Kawano, Ryuji Ohue-Kitano, Ikuo Kimura, Toru Nakazawa

    GLIA　71　(11)　2609-2622　2023年11月

    DOI： 10.1002/glia.24442 　

    ISSN：0894-1491

    eISSN：1098-1136

  19. DPP-4 Inhibitors Attenuate Fibrosis After Glaucoma Filtering Surgery by Suppressing the TGF-β/Smad Signaling Pathway. 国際誌

    Masaaki Yoshida, Taiki Kokubun, Kota Sato, Satoru Tsuda, Yu Yokoyama, Noriko Himori, Toru Nakazawa

    Investigative ophthalmology & visual science　64　(10)　2-2　2023年7月3日

    DOI： 10.1167/iovs.64.10.2 　

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    PURPOSE: This study investigated the effect of dipeptidyl peptidase-4 inhibitors (DPP-4is) on fibrosis after glaucoma filtering surgery with clinical data and an in vitro model that used transforming growth factor-β (TGF-β) to induce human Tenon's fibroblast (HTF) fibrosis. METHODS: The medical records of 41 eyes of 35 patients with diabetes with neovascular glaucoma (NVG) who received initial trabeculectomy were retrospectively reviewed. The surgical success rate was compared between cases that received (n = 23) and did not receive (n = 18) DPP-4i treatment for diabetes. The antifibrotic effects of linagliptin (a DPP-4i) were evaluated with quantitative real-time PCR for fibrosis markers (α-smooth muscle actin, collagen Iα, and fibronectin), a scratch assay, and a collagen gel contraction assay of primary cultured HTFs treated with TGF-β1 and linagliptin. Western blotting analysis was performed to evaluate the levels of phosphorylated Smad2 and Smad3 in the presence of linagliptin. RESULTS: The Kaplan-Meier curve for bleb survival was higher in patients who received DPP-4is (P = 0.017, log-rank test). The in vitro experiments demonstrated that treatment with linagliptin attenuated the elevated levels of fibrosis markers induced by TGF-β1 in HTFs. Linagliptin treatment also prevented the migration and gel contraction of HTFs. Linagliptin inhibited the phosphorylation of Smad2 and Smad3, which is the canonical pathway of TGF-β signaling. CONCLUSIONS: The current study indicates the potential effect of DPP-4is for maintaining bleb function after glaucoma filtering surgery in patients with diabetes with NVG. Our results demonstrate that linagliptin attenuates fibrotic change in HTFs by inhibiting TGF-β/Smad signaling.

  20. Reduced Plasma BDNF Levels in Normal Tension Glaucoma Compared to Open Angle Glaucoma. 国際誌

    Kota Sato, Naoko Takada, Amane Fujioka, Noriko Himori, Yu Yokoyama, Satoru Tsuda, Kazuko Omodaka, Tomoko Kirihara, Makoto Ishikawa, Hiroshi Kunikata, Toru Nakazawa

    Journal of glaucoma　2023年6月19日

    DOI： 10.1097/IJG.0000000000002257 　

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    AIMS: To evaluate differences in systemic BDNF levels between primary open-angle glaucoma (POAG) patients and normal-tension glaucoma (NTG) patients. METHODS: This study collected blood samples from 260 NTG patients, 220 age-matched POAG patients, and 120 age-matched cataract patients (as controls). BDNF levels were measured with an antibody-conjugated bead assay system (Luminex). RESULTS: We found that plasma BDNF levels in the NTG group were significantly lower than in the POAG and cataract control groups. There was no significant difference between the POAG and cataract groups. CONCLUSION: This result suggests that a low level of systemic BDNF may contribute to the pathogenesis of glaucoma in an IOP-independent manner.

  21. Neurosteroids as stress modulators and neurotherapeutics: lessons from the retina. 国際誌

    Yukitoshi Izumi, Makoto Ishikawa, Toru Nakazawa, Hiroshi Kunikata, Kota Sato, Douglas F Covey, Charles F Zorumski

    Neural regeneration research　18　(5)　1004-1008　2023年5月

    DOI： 10.4103/1673-5374.355752 　

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    Neurosteroids are rapidly emerging as important new therapies in neuropsychiatry, with one such agent, brexanolone, already approved for treatment of postpartum depression, and others on the horizon. These steroids have unique properties, including neuroprotective effects that could benefit a wide range of brain illnesses including depression, anxiety, epilepsy, and neurodegeneration. Over the past 25 years, our group has developed ex vivo rodent models to examine factors contributing to several forms of neurodegeneration in the retina. In the course of this work, we have developed a model of acute closed angle glaucoma that involves incubation of ex vivo retinas under hyperbaric conditions and results in neuronal and axonal changes that mimic glaucoma. We have used this model to determine neuroprotective mechanisms that could have therapeutic implications. In particular, we have focused on the role of both endogenous and exogenous neurosteroids in modulating the effects of acute high pressure. Endogenous allopregnanolone, a major stress-activated neurosteroid in the brain and retina, helps to prevent severe pressure-induced retinal excitotoxicity but is unable to protect against degenerative changes in ganglion cells and their axons under hyperbaric conditions. However, exogenous allopregnanolone, at a pharmacological concentration, completely preserves retinal structure and does so by combined effects on gamma-aminobutyric acid type A receptors and stimulation of the cellular process of macroautophagy. Surprisingly, the enantiomer of allopregnanolone, which is inactive at gamma-aminobutyric acid type A receptors, is equally retinoprotective and acts primarily via autophagy. Both enantiomers are also equally effective in preserving retinal structure and function in an in vivo glaucoma model. These studies in the retina have important implications for the ongoing development of allopregnanolone and other neurosteroids as therapeutics for neuropsychiatric illnesses.

  22. Fabrication of anti-inflammatory nano eye-drops composed of dexamethasone prodrugs

    Keita Tanita, Mai Iijima, Yoshitaka Koseki, Kota Sato, Toru Nakazawa, Hitoshi Kasai

    Molecular Crystals and Liquid Crystals　1-7　2023年2月23日

    出版者・発行元： Informa UK Limited

    DOI： 10.1080/15421406.2023.2180212 　

    ISSN：1542-1406

    eISSN：1563-5287

  23. Corrigendum: Glaucoma and microglia-induced neuroinflammation. 国際誌

    Makoto Ishikawa, Yukitoshi Izumi, Kota Sato, Taimu Sato, Charles F Zorumski, Hiroshi Kunikata, Toru Nakazawa

    Frontiers in ophthalmology　3　1332312-1332312　2023年

    DOI： 10.3389/fopht.2023.1332312 　

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    [This corrects the article DOI: 10.3389/fopht.2023.1132011.].

  24. The effect of a brinzolamide/brimonidine fixed combination on optic nerve head blood flow in rabbits. 国際誌

    Nana Takahashi, Kota Sato, Naoki Kiyota, Mai Yamazaki, Eriko Kunikane, Toru Nakazawa

    PloS one　18　(12)　e0295122　2023年

    DOI： 10.1371/journal.pone.0295122 　

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    PURPOSE: The purpose of this study was to investigate the effect of a 1% brinzolamide and 0.1% brimonidine fixed combination (BBFC) on ONH blood flow (BF) in rabbits. METHODS: A crossover study was conducted on pigmented rabbits; a physiological saline solution, brinzolamide, or BBFC was administered for eight days. ONH BF, intraocular pressure (IOP) and systemic parameters were measured before the eighth day's first dose and at 6, 9, 12, and 14 hours after the dose. ONH BF was assessed using laser speckle flowgraphy, and mean blur rate (MBR) values were calculated. The percentage against baseline of each parameter was calculated, and intergroup comparisons were performed at each time point. RESULTS: There were no significant differences in the percentage change in systemic parameters. At 6 hours after administration, the BBFC group showed a significantly higher percentage change in large vessel area-MBR (%MV) compared to the control group (98.6±16.8%MV vs. 81.3±7.9%MV, P = 0.03). On the other hand, the brinzolamide group did not show a significant difference. Both the brinzolamide and BBFC groups had significantly lower percentage change in IOP (%IOP) compared to the control group (90.6±5.0%IOP, 93.3±2.9%IOP, and 99.2±1.7%IOP, respectively, P < 0.01). CONCLUSION: BBFC effectively reduces IOP and mitigates diurnal fluctuation-induced decreases in ONH BF.

  25. Genetic variants associated with glaucomatous visual field loss in primary open-angle glaucoma. 国際誌

    Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie

    Scientific reports　12　(1)　20744-20744　2022年12月1日

    DOI： 10.1038/s41598-022-24915-x 　

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    Primary open-angle glaucoma (POAG) is characterized by a progressive optic neuropathy with visual field loss. To investigate the genetic variants associated with visual field loss in POAG, Japanese POAG patients (n = 426) and control subjects (n = 246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (optic nerve-related genetic variants). The genetic risk score (GRS) of the 17 IOP-related and five optic nerve-related genetic variants was calculated, and the associations between the GRS and the mean deviation (MD) of automated static perimetry as an indicator of the severity of visual field loss and pattern standard deviation (PSD) as an indicator of the focal disturbance were evaluated. There was a significant association (Beta = - 0.51, P = 0.0012) between the IOP-related GRS and MD. The severity of visual field loss may depend on the magnitude of IOP elevation induced by additive effects of IOP-related genetic variants. A significant association (n = 135, Beta = 0.65, P = 0.0097) was found between the optic nerve-related, but not IOP-related, GRS and PSD. The optic nerve-related (optic nerve vulnerability) and IOP-related (IOP elevation) genetic variants may play an important role in the focal and diffuse visual field loss respectively. To our knowledge, this is the first report to show an association between additive effects of genetic variants predisposing to POAG and glaucomatous visual field loss, including severity and focal/diffuse disturbance of visual field loss, in POAG.

  26. Changes in glial cells and neurotrophic factors due to rotenone-induced oxidative stress in Nrf2 knockout mice. 国際誌

    Maki Inoue-Yanagimachi, Noriko Himori, Keiko Uchida, Hiroshi Tawarayama, Kota Sato, Masayuki Yamamoto, Kazuhiko Namekata, Takayuki Harada, Toru Nakazawa

    Experimental eye research　109314-109314　2022年11月15日

    DOI： 10.1016/j.exer.2022.109314 　

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    Glaucoma is one of the most common causes of blindness worldwide. It is thought to be a multifactorial disease with underlying mechanisms that include mitochondrial dysfunction and oxidative stress. Here, we used NF-E2 related factor 2 (Nrf2) knockout (KO) mice, which are vulnerable to oxidative stress, to examine a neuroprotective effect against oxidative stress due to rotenone, a mitochondrial complex I inhibitor. Wild-type (WT) and Nrf2 KO mice received an oral solution of rotenone for 30 days. We then extracted the retinas and performed immunohistochemistry and quantitative RT-PCR. We also prepared a primary Müller cell culture of samples from each mouse, added 30 μM rotenone, and then measured cell viability, cytotoxicity and CellRox absorbance. We also examined gene expression. We found a significant increase in the number of 8-OHdG-positive retinal ganglion cells (RGCs) after rotenone administration in both the WT and Nrf2 KO mice. There was no difference in the number of RNA-binding protein with multiple splicing (RBPMS)-positive RGCs in the WT and Nrf2 KO mice, but Nrf2 KO mice that were given rotenone had significantly less retinal gene expression of RBPMS than Nrf2 KO mice given a control. Moreover, there was significantly higher mRNA gene expression of vimentin and glial fibrillary acidic protein (GFAP) in Nrf2 KO mice that received rotenone than WT mice that received rotenone. A statistical analysis of the in vitro experiment showed that cell viability was lower, cytotoxicity was higher, and oxidative stress was higher in the Müller cells of the Nrf2 KO mice than the WT mice. Finally, brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) were significantly higher in the Müller cells of the Nrf2 KO mice than the WT mice. These findings suggest that in Nrf2 KO mice under oxidative stress caused by rotenone, temporary neurotrophic factors are secreted from the Müller cells, conferring neuroprotection in these cells.

  27. A Plant-Derived Antioxidant Supplement Prevents the Loss of Retinal Ganglion Cells in the Retinas of NMDA-Injured Mice. 国際誌

    Shigeto Maekawa, Kota Sato, Taiki Kokubun, Noriko Himori, Takeshi Yabana, Michiko Ohno-Oishi, Ge Shi, Kazuko Omodaka, Toru Nakazawa

    Clinical ophthalmology (Auckland, N.Z.)　16　823-832　2022年

    DOI： 10.2147/OPTH.S354958 　

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    Purpose: To investigate the effect of plant-derived antioxidant compounds, identified with primary culture screening, on retinal ganglion cell (RGC) survival in mice under excitotoxic conditions. Additionally, to determine the effect of these compounds on the involvement of calpain inactivation. Materials and Methods: Plant-derived antioxidant compounds including hesperidin, crocetin, and Tamarindus indica were administrated orally to C57BL/6J mice. The levels of lipid oxidation and calpain activation were assessed with a TBARS assay and western blotting. RGC survival was evaluated with a TUNEL assay and RBPMS immunostaining after intravitreal injection of NMDA. Results: Plant-derived antioxidant compounds significantly ameliorated the increase in the level of MDA in the retinas after NMDA injury. Cleaved α-fodrin fragments were detected in the NMDA-injured retinas, and these fragments were significantly lower in mice that received the plant-derived antioxidant compounds. The plant-derived antioxidants also ameliorated increases in TUNEL-positive cells and RGC death after NMDA injection. Conclusion: These results indicate that oral administration of plant-derived antioxidant compounds such as hesperidin, crocetin, and Tamarindus indica suppressed RGC death. This oral supplementation decreased lipid oxidation and excessive calpain activation in NMDA-injured retinas. Thus, our newly developed antioxidant supplement has a potential role in neuroprotective treatment for retinal diseases, such as glaucoma.

  28. The Enantiomer of Allopregnanolone Prevents Pressure-Mediated Retinal Degeneration Via Autophagy. 国際誌

    Makoto Ishikawa, Toru Nakazawa, Hiroshi Kunikata, Kota Sato, Takeshi Yoshitomi, Kathiresan Krishnan, Douglas F Covey, Charles F Zorumski, Yukitoshi Izumi

    Frontiers in pharmacology　13　855779-855779　2022年

    DOI： 10.3389/fphar.2022.855779 　

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    In an ex vivo rat ocular hypertension (OHT) model, the neurosteroid allopregnanolone (AlloP) exerts neuroprotective effects via enhancement of both GABAA receptors and autophagy. We now examine whether its enantiomer (ent-AlloP), which is largely inactive at GABA receptors, offers similar neuroprotection in ex vivo and in vivo rat OHT models. Ex vivo rat retinal preparations were incubated in a hyperbaric condition (10 and 75 mmHg) for 24 h. An in vivo ocular hypertension (OHT) model was induced by intracameral injection of polystyrene microbeads. We examined pharmacological effects of AlloP, ent-AlloP, picrotoxin (a GABAA receptor antagonist), and 3-MA (an autophagy inhibitor) histologically and biochemically. We found that both AlloP and ent-AlloP have marked neuroprotective effects in the retina, but effects of the unnatural enantiomer are independent of GABAA receptors. Electron microscopic analyses show that pressure elevation significantly increased autophagosomes (APs) in the nerve fiber layer and addition of AlloP also increased APs and degenerative autophagic vacuoles (AVds). ent-AlloP markedly increased APs and AVds compared to AlloP. Examination of LC3B-II and SQSTM1 protein levels using immunoblotting revealed that AlloP increased LC3B-II, and ent-AlloP further enhanced LC3B-II and suppressed SQSTM1, indicating that autophagy is a major mechanism underlying neuroprotection by ent-AlloP. In an rat in vivo OHT model, single intravitreal ent-AlloP injection prevented apoptotic cell death of retinal ganglion cells similar to AlloP. However, even in this model, ent-AlloP was more effective in activating autophagy than AlloP. We conclude that ent-AlloP may be a prototype of potential therapeutic for treatment of glaucoma as an autophagy enhancer without affecting GABA receptors.

  29. CHOP deletion and anti-neuroinflammation treatment with hesperidin synergistically attenuate NMDA retinal injury in mice. 国際誌

    Kota Sato, Taimu Sato, Michiko Ohno-Oishi, Mikako Ozawa, Shigeto Maekawa, Yukihiro Shiga, Takeshi Yabana, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Kosuke Fujita, Koji M Nishiguchi, Shi Ge, Toru Nakazawa

    Experimental eye research　213　108826-108826　2021年12月

    DOI： 10.1016/j.exer.2021.108826 　

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    Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

  30. A hypomorphic variant in EYS detected by genome-wide association study contributes toward retinitis pigmentosa. 国際誌

    Koji M Nishiguchi, Fuyuki Miya, Yuka Mori, Kosuke Fujita, Masato Akiyama, Takashi Kamatani, Yoshito Koyanagi, Kota Sato, Toru Takigawa, Shinji Ueno, Misato Tsugita, Hiroshi Kunikata, Katarina Cisarova, Jo Nishino, Akira Murakami, Toshiaki Abe, Yukihide Momozawa, Hiroko Terasaki, Yuko Wada, Koh-Hei Sonoda, Carlo Rivolta, Tatsuhiko Tsunoda, Motokazu Tsujikawa, Yasuhiro Ikeda, Toru Nakazawa

    Communications biology　4　(1)　140-140　2021年1月29日

    DOI： 10.1038/s42003-021-01662-9 　

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    The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10-8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

  31. Glutathione Trisulfide Prevents Lipopolysaccharide-induced Inflammatory Gene Expression in Retinal Pigment Epithelial Cells. 国際誌

    Hiroshi Tawarayama, Noriyuki Suzuki, Maki Inoue-Yanagimachi, Noriko Himori, Satoru Tsuda, Kota Sato, Tomoaki Ida, Takaaki Akaike, Hiroshi Kunikata, Toru Nakazawa

    Ocular immunology and inflammation　1-12　2020年11月20日

    DOI： 10.1080/09273948.2020.1833224 　

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    We investigated the effects of glutathione trisulfide (GSSSG) on lipopolysaccharide (LPS)-induced inflammatory gene expression in immortalized ARPE-19, and primary human and mouse retinal pigment epithelial (RPE) cells. Sulfane sulfur molecules were significantly increased in GSSSG-treated ARPE-19 cells. GSSSG prevented the LPS-induced upregulation of interleukin (IL)-1β, IL-6, and C-C motif chemokine ligand 2 (CCL2) in ARPE-19/primary RPE cells. Moreover, GSSSG prevented the activation of the nuclear factor-kappa B p65 subunit, and promoted the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in LPS-treated ARPE-19 cells. ERK1/2 inhibition prevented the GSSSG-mediated inhibition of LPS-induced IL-6 and CCL2 upregulation. Additionally, ERK1/2 activation prevented the upregulation of these genes in the absence of GSSSG. Knockdown of HMOX1 or NRF2, known as anti-oxidative genes, did not affect the activity of GSSSG in the context of LPS stimulation. These findings suggest that GSSSG attenuates LPS-induced inflammatory gene expression via ERK signaling hyperactivation, independently of the NRF2/HMOX1 pathway.

  32. Companion diagnosis for retinal neuroprotective treatment by real-time imaging of calpain activation using a novel fluorescent probe. 国際誌 査読有り

    Toshifumi Asano, Yuri Nagayo, Satoru Tsuda, Azusa Ito, Wataru Kobayashi, Kosuke Fujita, Kota Sato, Koji M Nishiguchi, Hiroshi Kunikata, Hiroyoshi Fujioka, Mako Kamiya, Yasuteru Urano, Toru Nakazawa

    Bioconjugate chemistry　31　(9)　2241-2251　2020年8月25日

    DOI： 10.1021/acs.bioconjchem.0c00435 　

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    Calpain activation induces retinal ganglion cell (RGC) death, while calpain inhibition suppresses RGC death, in animal studies. However, the role of calpain in human retinal disease is unclear. This study investigated a new strategy to study the role of calpain based on real-time imaging. We synthesized a novel fluorescent probe for calpain, acetyl-L-leucyl-L-methionine-hydroxymethyl rhodamine green (Ac-LM-HMRG) and used it for real-time imaging of calpain activation. The toxicity of Ac-LM-HMRG was evaluated with a lactate dehydrogenase (LDH) cytotoxicity assay, retinal sections, and electroretinograms (ERG). Here, we performed real-time imaging of calpain activation in a rat model. First, we administered N-methyl-D-aspartate (NMDA) to induce retinal injury. Twenty minutes later, we administered an intravitreal injection of Ac-LM-HMRG. Real-time imaging was then completed with a non-invasive confocal scanning laser ophthalmoscope. The inhibitory effect of SNJ-1945 against calpain activation was also examined with the same real-time imaging method. Ac-LM-HMRG had no toxic effects. The number of Ac-LM-HMRG-positive cells in real-time imaging significantly increased after NMDA injury, and SNJ-1945 significantly lowered the number of Ac-LM-HMRG-positive cells. Real-time imaging with Ac-LM-HMRG was able to quickly quantify the NMDA-induced activation of calpain and the inhibitory effect of SNJ-1945. This technique, used as a companion diagnostic system, may aid research into the development of new neuroprotective therapies.

  33. Effect of the chemical structure on the drug release from brinzolamide based nano eye-drops

    Yoshitaka Koseki, Yoshikazu Ikuta, Kota Sato, Shigenobu Aoyagi, Satoshi Inada, Tsunenobu Onodera, Hidetoshi Oikawa, Koji M. Nishiguchi, Toru Nakazawa, Hitoshi Kasai

    Molecular Crystals and Liquid Crystals　706　(1)　122-128　2020年7月23日

    出版者・発行元： Informa UK Limited

    DOI： 10.1080/15421406.2020.1743447 　

    ISSN：1542-1406

    eISSN：1563-5287

  34. Genetic variants associated with the onset and progression of primary open-angle glaucoma. 国際誌 査読有り

    Fumihiko Mabuchi, Nakako Mabuchi, Yoichi Sakurada, Seigo Yoneyama, Kenji Kashiwagi, Hiroyuki Iijima, Zentaro Yamagata, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Koji M Nishiguchi, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie

    American journal of ophthalmology　215　135-140　2020年3月23日

    DOI： 10.1016/j.ajo.2020.03.014 　

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    PURPOSE: To investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n=505) and control subjects (n=246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. RESULTS: There was a significant association (P=0.014, odds ratio: 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P=0.0014, Beta=-0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. CONCLUSIONS: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role its progression (age at the diagnosis of glaucoma).

  35. A pyruvate dehydrogenase kinase inhibitor prevents retinal cell death and improves energy metabolism in rat retinas after ischemia/reperfusion injury. 国際誌 査読有り

    Kota Sato, Seiya Mochida, Daisuke Tomimoto, Takahiro Konuma, Naoki Kiyota, Satoru Tsuda, Yukihiro Shiga, Kazuko Omodaka, Toru Nakazawa

    Experimental eye research　193　107997-107997　2020年3月9日

    DOI： 10.1016/j.exer.2020.107997 　

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    We aimed to assess the neuroprotective effect of a pyruvate dehydrogenase kinase (PDK) inhibitor, Nov3r after ischemia/reperfusion (IR) injury in rats. IR injury was induced by applying 150 mmHg of intraocular pressure for 50 min. Nov3r was orally administered (100 mg/kg) 3 h before and 24 h after IR injury. TUNEL-positive cells increased and immunoreactive RBPMS-positive cells decreased in the rat retinas after IR injury. Administration of Nov3r significantly ameliorated the increase in TUNEL-positive cells and prevented the RBPMS-positive cell decrease. Similarly, the number of IR-induced Iba1-positive microglial cells was significantly reduced with Nov3r treatment. Among metabolic parameters, IR damage induced the elevation of lactate and pyruvate, and the reduction of ATP. Oral administration of Nov3r ameliorated these changes. Our data suggest that the Nov3r had a retinal neuroprotective effect in IR injury in rats. This finding suggests that the regulation of pyruvate dehydrogenase (PDH) activity has potential therapeutic value by enabling metabolic reprograming in diseases associated with ischemic retinal damage, such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy and glaucoma.

  36. Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. 国際誌 査読有り

    Yoichi Wada, Atsuo Kikuchi, Akimune Kaga, Naoki Shimizu, Junya Ito, Ryo Onuma, Fumiyoshi Fujishima, Eriko Totsune, Ryo Sato, Tetsuya Niihori, Matsuyuki Shirota, Ryo Funayama, Kota Sato, Toru Nakazawa, Keiko Nakayama, Yoko Aoki, Setsuya Aiba, Kiyotaka Nakagawa, Shigeo Kure

    PLoS genetics　16　(2)　e1008628　2020年2月26日

    DOI： 10.1371/journal.pgen.1008628 　

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    Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

  37. The Sustained Release of Tafluprost with a Drug Delivery System Prevents the Axonal Injury-induced Loss of Retinal Ganglion Cells in Rats. 国際誌 査読有り

    Kota Sato, Yurika Nakagawa, Kazuko Omodaka, Hiroyuki Asada, Shinobu Fujii, Kenji Masaki, Toru Nakazawa

    Current eye research　1-10　2020年1月29日

    DOI： 10.1080/02713683.2020.1715446 　

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    Purpose: To investigated whether a new drug delivery system (DDS) could enable the controlled release of tafluprost and suppress retinal ganglion cell (RGC) death in rats after optic nerve transection (ONT).Methods: A DDS containing 0.04%, 0.20% or 1.00% tafluprost, or vehicle, was injected intravitreally in 8-12-week-old male Sprague-Dawley rats 7 days before ONT, and the retinas were extracted 7 days after ONT. For comparison, eye drops containing 0.0015% tafluprost or vehicle were used once a day. The extracted retinas were analyzed with liquid chromatography-tandem mass spectrometry, immunohistochemistry and western blotting.Results: The level of tafluprost acid in the groups that received the 0.20% and 1.00% tafluprost DDSs was stable, and higher than the maximum concentration in the eye drop group, even after 14 days. In the retinas treated with the 1.00% tafluprost DDS, the active form of the drug had a high concentration (~50 times higher than eye drops), but no significant IOP difference compared with its vehicle in this study. The 1.00% tafluprost DDS group also had less cleaved α-fodrin and fewer c-Jun-positive cells than the vehicle DDS group.Conclusions: This study found that a newly developed DDS allowed the controlled release of tafluprost and prevented the loss of RGCs after ONT IOP independently. The duration of drug action on the target site was longer with a tafluprost DDS than with topical instillation and should therefore reduce problems related to lack of patient compliance. This system may also enable new treatments to prevent RGC degeneration in diseases such as glaucoma.

  38. In vivo and in vitro knockout system labelled using fluorescent protein via microhomology-mediated end joining. 査読有り

    Katayama S, Sato K, Nakazawa T

    Life science alliance　3　(1)　2020年1月

    DOI： 10.26508/lsa.201900528 　

  39. The DNA topoisomerase II inhibitor amsacrine as a novel candidate adjuvant in a model of glaucoma filtration surgery. 国際誌 査読有り

    Kotaro Yamamoto, Taiki Kokubun, Kota Sato, Takahiro Akaishi, Atsushi Shimazaki, Masatsugu Nakamura, Yukihiro Shiga, Satoru Tsuda, Kazuko Omodaka, Hideyuki Saya, Toru Nakazawa

    Scientific reports　9　(1)　19288-19288　2019年12月17日

    DOI： 10.1038/s41598-019-55365-7 　

    詳細を見る 詳細を閉じる

    Treatments for refractory glaucoma include trabeculectomy, in which a filtering bleb is created to reduce aqueous pressure. Mitomycin C (MMC) is often used as an adjuvant to reduce post-trabeculectomy bleb scarring and consequent failure. However, scarring sometimes still occurs. Thus, we searched for more effective trabeculectomy adjuvants with high-throughput screening (HTS) of a library of 1,165 off-patent drug compounds. This revealed that amsacrine (AMSA), a DNA topoisomerase II (TOP2) inhibitor, was the top candidate. Compared to MMC, rabbits that underwent trabeculectomy with 10% AMSA had lower IOP at 42, 56, and 70 days (P < 0.01 at all measurement points) and a higher bleb score at 28, 42, 56, and 70 days (P =  < 0.01, 0.04, 0.04, and < 0.01, respectively). Compared to saline, rabbits that received 1% AMSA also had lower IOP and better bleb score at all time points, without a sharp drop in IOP just after surgery (all P < 0.01). Both effects were milder than MMC at 7 days (P = 0.02 and <0.01, respectively). Thus, this study showed that HTS may help identify new, promising uses for off-patent drugs. Furthermore, trabeculectomy with AMSA at a suitable concentration may improve the prognosis after trabeculectomy compared to MMC.

  40. In vivo imaging of the light response in mouse retinal ganglion cells based on a neuronal activity-dependent promoter. 査読有り

    Fujita K, Nishiguchi KM, Sato K, Nakagawa Y, Nakazawa T

    Biochemical and biophysical research communications　2019年10月

    DOI： 10.1016/j.bbrc.2019.10.155 　

    ISSN：0006-291X

  41. Bilateral Necrotizing Herpes Simplex Keratitis in an Immunocompetent Patient With Genetic Analysis of Human Simplex Virus 1. 国際誌 査読有り

    Yoshida M, Hosogai M, Yokokura S, Sato K, Hariya T, Kobayashi W, Okabe T, Todokoro D, Nakazawa T

    Cornea　38　(9)　1185-1188　2019年9月1日

    出版者・発行元：

    DOI： 10.1097/ICO.0000000000002026 　

    ISSN：1536-4798

  42. Assessing retinal ganglion cell death and neuroprotective agents using real time imaging. 国際誌 査読有り

    Ito A, Tsuda S, Kunikata H, Toshifumi A, Sato K, Nakazawa T

    Brain research　1714　65-72　2019年7月

    DOI： 10.1016/j.brainres.2019.02.008 　

    ISSN：0006-8993

  43. The relationship between glutathione levels in leukocytes and ocular clinical parameters in glaucoma. 国際誌 査読有り

    Takeshi Yabana, Kota Sato, Yukihiro Shiga, Noriko Himori, Kazuko Omodaka, Toru Nakazawa

    PloS one　14　(12)　e0227078　2019年

    DOI： 10.1371/journal.pone.0227078 　

    詳細を見る 詳細を閉じる

    PURPOSE: To investigate the effect of mitochondrial dysfunction on the autoregulation of blood flow, by measuring levels of glutathione, an indicator of mitochondrial dysfunction, in glaucoma patients. METHODS: Fifty-six OAG patients and 21 age-matched controls underwent a blood assay. Mitochondrial function was measured according to the levels of total glutathione (t-GSH), reduced GSH (GSH), and oxidized GSH (GSSG, glutathione disulfide) in peripheral blood mononuclear cells. Ocular blood flow in the optic nerve head was assessed with laser speckle flowgraphy parameters, including acceleration time index (ATI). We determined correlations between these measurements and other clinical parameters. Furthermore, we investigated the association between glutathione levels and glaucoma with a logistic regression analysis. Finally, we calculated the area under the receiver operating characteristic (ROC) curve in order to determine the power of redox index (the log GSH/GSSG ratio) to distinguish the groups. RESULTS: OAG patients demonstrated significantly higher GSSG levels and a lower redox index than the controls (p = 0.01, p = 0.01, respectively), but total GSH and reduced GSH levels were similar in the OAG subjects and controls (p = 0.80, p = 0.94, respectively). Additionally, redox index was significantly correlated with mean deviation (MD) of the visual field (r = 0.29, p = 0.03) and ATI (r = -0.30, p = 0.03). Multiple linear regression analysis showed that redox index contributed to MD (p = 0.02) and ATI (p = 0.04). The receiver operating characteristic curve (AUC) analysis suggested that redox index could differentiate between control eyes and eyes with glaucoma (AUC; 0.70: 95% interval; 0.57-0.84). The cutoff point for redox index to maximize its sensitivity and specificity was 2.0 (sensitivity: 91.1%, specificity: 42.9%). CONCLUSIONS: These results suggest that redox index is lower in OAG patients than in controls. Thus, it is possible that mitochondrial dysfunction contributes to glaucoma pathogenesis by causing vascular alterations.

  44. The findings of optical coherence tomography of retinal degeneration in relation to the morphological and electroretinographic features in RPE65-/- mice. 査読有り

    Tanabu R, Sato K, Monai N, Yamauchi K, Gonome T, Xie Y, Takahashi S, Ishiguro SI, Nakazawa M

    PloS one　14　(1)　e0210439　2019年

    DOI： 10.1371/journal.pone.0210439 　

  45. The effectiveness of colchicine combined with mitomycin C to prolong bleb function in trabeculectomy in rabbits. 国際誌 査読有り

    Kokubun T, Yamamoto K, Sato K, Akaishi T, Shimazaki A, Nakamura M, Shiga Y, Tsuda S, Omodaka K, Nakazawa T

    PloS one　14　(3)　e0213811　2019年

    DOI： 10.1371/journal.pone.0213811 　

  46. Reliable detection of low visual acuity in mice with pattern visually evoked potentials. 査読有り

    Tokashiki N, Nishiguchi KM, Fujita K, Sato K, Nakagawa Y, Nakazawa T

    Scientific reports　8　(1)　15948　2018年10月

    DOI： 10.1038/s41598-018-34413-8 　

  47. Association between mitochondrial DNA damage and ocular blood flow in patients with glaucoma. 国際誌 査読有り

    Inoue-Yanagimachi M, Himori N, Sato K, Kokubun T, Asano T, Shiga Y, Tsuda S, Kunikata H, Nakazawa T

    The British journal of ophthalmology　103　(8)　1060-1065　2018年9月

    DOI： 10.1136/bjophthalmol-2018-312356 　

    ISSN：0007-1161

  48. Ecel1 Knockdown With an AAV2-Mediated CRISPR/Cas9 System Promotes Optic Nerve Damage-Induced RGC Death in the Mouse Retina. 国際誌 査読有り

    Sato K, Shiga Y, Nakagawa Y, Fujita K, Nishiguchi KM, Tawarayama H, Murayama N, Maekawa S, Yabana T, Omodaka K, Katayama S, Feng Q, Tsuda S, Nakazawa T

    Investigative ophthalmology & visual science　59　(10)　3943-3951　2018年8月

    DOI： 10.1167/iovs.18-23784 　

    ISSN：0146-0404

  49. Metabolomic changes in the mouse retina after optic nerve injury. 国際誌 査読有り

    Sato K, Saigusa D, Saito R, Fujioka A, Nakagawa Y, Nishiguchi KM, Kokubun T, Motoike IN, Maruyama K, Omodaka K, Shiga Y, Uruno A, Koshiba S, Yamamoto M, Nakazawa T

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

    DOI： 10.1038/s41598-018-30464-z 　

  50. Ciliary neurotrophic factor (CNTF) protects retinal cone and rod photoreceptors by suppressing excessive formation of the visual pigments. 査読有り

    Li S, Sato K, Gordon WC, Sendtner M, Bazan NG, Jin M

    The Journal of biological chemistry　293　(39)　15256-15268　2018年8月

    DOI： 10.1074/jbc.RA118.004008 　

    ISSN：0021-9258

  51. Diagnosing superinfection keratitis with multiplex polymerase chain reaction. 国際誌 査読有り

    Yoshida M, Hariya T, Yokokura S, Maruyama K, Sato K, Sugita S, Tomaru Y, Shimizu N, Nakazawa T

    Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy　24　(12)　1004-1008　2018年7月

    DOI： 10.1016/j.jiac.2018.06.012 　

    ISSN：1341-321X

  52. Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma. 査読有り

    Shiga Y, Akiyama M, Nishiguchi KM, Sato K, Shimozawa N, Takahashi A, Momozawa Y, Hirata M, Matsuda K, Yamaji T, Iwasaki M, Tsugane S, Oze I, Mikami H, Naito M, Wakai K, Yoshikawa M, Miyake M, Yamashiro K, Japan, Glaucoma Society, Omics Group, JGS-OG, Kashiwagi K, Iwata T, Mabuchi F, Takamoto M, Ozaki M, Kawase K, Aihara M, Araie M, Yamamoto T, Kiuchi Y, Nakamura M, Ikeda Y, Sonoda KH, Ishibashi T, Nitta K, Iwase A, Shirato S, Oka Y, Satoh M, Sasaki M, Fuse N, Suzuki Y, Cheng CY, Khor CC, Baskaran M, Perera S, Aung T, Vithana EN, Cooke Bailey JN, Kang JH, Pasquale LR, Haines JL, NEIGHBORHOOD Consortium, Wiggs JL, Burdon KP, Gharahkhani P, Hewitt AW, Mackey DA, MacGregor S, Craig JE, Allingham RR, Hauser M, Ashaye A, Budenz DL, Akafo S, Williams SEI, Kamatani Y, Nakazawa T, Kubo M

    Human molecular genetics　27　(8)　1486-1496　2018年4月

    出版者・発行元：

    DOI： 10.1093/hmg/ddy053 　

    ISSN：0964-6906

  53. Interleukin-6 plays a crucial role in the development of subretinal fibrosis in a mouse model. 査読有り

    Sato K, Takeda A, Hasegawa E, Jo YJ, Arima M, Oshima Y, Ryoji Y, Nakazawa T, Yuzawa M, Nakashizuka H, Shimada H, Kimura K, Ishibashi T, Sonoda KH

    Immunological medicine　41　(1)　23-29　2018年3月

    DOI： 10.1080/09114300.2018.1451609 　

  54. The neuroprotective effect of hesperidin in NMDA-induced retinal injury acts by suppressing oxidative stress and excessive calpain activation. 査読有り

    Maekawa S, Sato K, Fujita K, Daigaku R, Tawarayama H, Murayama N, Moritoh S, Yabana T, Shiga Y, Omodaka K, Maruyama K, Nishiguchi KM, Nakazawa T

    Scientific reports　7　(1)　6885　2017年7月

    出版者・発行元：

    DOI： 10.1038/s41598-017-06969-4 　

    ISSN：2045-2322

  55. Multiplex polymerase chain reaction for pathogen detection in donor/recipient corneal transplant tissue and donor storage solution 査読有り

    Takehiro Hariya, Kazuichi Maruyama, Sunao Sugita, Masayo Takahashi, Shunji Yokokura, Kota Sato, Yasuhiro Tomaru, Norio Shimizu, Toru Nakazawa

    SCIENTIFIC REPORTS　7　(1)　5973　2017年7月

    DOI： 10.1038/s41598-017-06344-3 　

    ISSN：2045-2322

  56. Creation of nano eye-drops and effective drug delivery to the interior of the eye 査読有り

    Yoshikazu Ikuta, Shigenobu Aoyagi, Yuji Tanaka, Kota Sato, Satoshi Inada, Yoshitaka Koseki, Tsunenobu Onodera, Hidetoshi Oikawa, Hitoshi Kasai

    SCIENTIFIC REPORTS　7　44229　2017年3月

    DOI： 10.1038/srep44229 　

    ISSN：2045-2322

  57. Metabolomic profiling of reactive persulfides and polysulfides in the aqueous and vitreous humors 査読有り

    Hiroshi Kunikata, Tomoaki Ida, Kota Sato, Naoko Aizawa, Tomohiro Sawa, Hiroshi Tawarayama, Namie Murayama, Shigemoto Fujii, Takaaki Akaike, Toru Nakazawa

    SCIENTIFIC REPORTS　7　41984　2017年2月

    DOI： 10.1038/srep41984 　

    ISSN：2045-2322

  58. The neuroprotective effect of latanoprost acts via klotho-mediated suppression of calpain activation after optic nerve transection 査読有り

    Kotaro Yamamoto, Kota Sato, Masayoshi Yukita, Masayuki Yasuda, Kazuko Omodaka, Morin Ryu, Kosuke Fujita, Koji M. Nishiguchi, Shigeki Machida, Toru Nakazawa

    JOURNAL OF NEUROCHEMISTRY　140　(3)　495-508　2017年2月

    DOI： 10.1111/jnc.13902 　

    ISSN：0022-3042

    eISSN：1471-4159

  59. Genetic analysis of Japanese primary open-angle glaucoma patients and clinical characterization of risk alleles near CDKN2B-AS1, SIX6 and GAS7. 査読有り

    Shiga Y, Nishiguchi KM, Kawai Y, Kojima K, Sato K, Fujita K, Takahashi M, Omodaka K, Araie M, Kashiwagi K, Aihara M, Iwata T, Mabuchi F, Takamoto M, Ozaki M, Kawase K, Fuse N, Yamamoto M, Yasuda J, Nagasaki M, Nakazawa T, Japan, Glaucoma Society, Omics Group, JGS-OG

    PloS one　12　(12)　e0186678　2017年

    出版者・発行元：

    DOI： 10.1371/journal.pone.0186678 　

    ISSN：1932-6203

  60. Brimonidine Enhances the Electrophysiological Response of Retinal Ganglion Cells through the Trk-MAPK/ERK and PI3K Pathways in Axotomized Eyes 査読有り

    Masayoshi Yukita, Kazuko Omodaka, Shigeki Machida, Masayuki Yasuda, Kota Sato, Kazuichi Maruyama, Koji M. Nishiguchi, Toru Nakazawa

    CURRENT EYE RESEARCH　42　(1)　125-133　2017年1月

    DOI： 10.3109/02713683.2016.1153112 　

    ISSN：0271-3683

    eISSN：1460-2202

  61. Bilberry extract administration prevents retinal ganglion cell death in mice via the regulation of chaperone molecules under conditions of endoplasmic reticulum stress. 査読有り

    Nakamura O, Moritoh S, Sato K, Maekawa S, Murayama N, Himori N, Omodaka K, Sogon T, Nakazawa T

    Clinical ophthalmology (Auckland, N.Z.)　11　1825-1834　2017年

    出版者・発行元：

    DOI： 10.2147/OPTH.S145159 　

    ISSN：1177-5467

  62. Interphotoreceptor Retinoid-Binding Protein Mitigates Cellular Oxidative Stress and Mitochondrial Dysfunction Induced by All-trans-Retinal 査読有り

    Minsup Lee, Songhua Li, Kota Sato, Minghao Jin

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　57　(4)　1553-1562　2016年4月

    DOI： 10.1167/iovs.15-18551 　

    ISSN：0146-0404

    eISSN：1552-5783

  63. Topical ocular dexamethasone decreases intraocular pressure and body weight in rats. 査読有り

    Sato K, Nishiguchi KM, Maruyama K, Moritoh S, Fujita K, Ikuta Y, Kasai H, Nakazawa T

    Journal of negative results in biomedicine　15　(1)　5　2016年3月

    出版者・発行元：

    DOI： 10.1186/s12952-016-0048-x 　

    ISSN：1477-5751

  64. Artemin Augments Survival and Axon Regeneration in Axotomized Retinal Ganglion Cells 査読有り

    Kazuko Omodaka, Takuji Kurimoto, Orie Nakamura, Kota Sato, Masayuki Yasuda, Yuji Tanaka, Noriko Himori, Yu Yokoyama, Toru Nakazawa

    JOURNAL OF NEUROSCIENCE RESEARCH　92　(12)　1637-1646　2014年12月

    DOI： 10.1002/jnr.23449 　

    ISSN：0360-4012

    eISSN：1097-4547

  65. Neuroprotective effect against axonal damage-induced retinal ganglion cell death in apolipoprotein E-deficient mice through the suppression of kainate receptor signaling 査読有り

    Kazuko Omodaka, Koji M. Nishiguchi, Masayuki Yasuda, Yuji Tanaka, Kota Sato, Orie Nakamura, Kazuichi Maruyama, Toru Nakazawa

    BRAIN RESEARCH　1586　203-212　2014年10月

    DOI： 10.1016/j.brainres.2014.08.053 　

    ISSN：0006-8993

    eISSN：1872-6240

  66. Receptor Interacting Protein Kinase-Mediated Necrosis Contributes to Cone and Rod Photoreceptor Degeneration in the Retina Lacking Interphotoreceptor Retinoid-Binding Protein 査読有り

    Kota Sato, Songhua Li, William C. Gordon, Jibao He, Gregory I. Liou, James M. Hill, Gabriel H. Travis, Nicolas G. Bazan, Minghao Jin

    JOURNAL OF NEUROSCIENCE　33　(44)　17458-17468　2013年10月

    DOI： 10.1523/JNEUROSCI.1380-13.2013 　

    ISSN：0270-6474

  67. M-opsin protein degradation is inhibited by MG-132 in Rpe65⁻/⁻ retinal explant culture. 査読有り

    Sato K, Ozaki T, Ishiguro S, Nakazawa M

    Molecular vision　18　(157-61)　1516-1525　2012年6月

    ISSN：1090-0535

  68. A Novel Compound Heterozygous Mutation in the CYP4V2 Gene in a Japanese Patient with Bietti's Crystalline Corneoretinal Dystrophy. 査読有り

    Yokoi Y, Sato K, Aoyagi H, Takahashi Y, Yamagami M, Nakazawa M

    Case reports in ophthalmology　2　(3)　296-301　2011年9月

    DOI： 10.1159/000331885 　

    ISSN：1663-2699

  69. Inhibitory effects of trehalose on fibroblast proliferation and implications for ocular surgery 査読有り

    Kimio Takeuchi, Mitsuru Nakazawa, Yuichi Ebina, Kota Sato, Tomomi Metoki, Yasuhiro Miyagawa, Tadashi Ito

    EXPERIMENTAL EYE RESEARCH　91　(5)　567-577　2010年11月

    DOI： 10.1016/j.exer.2010.07.002 　

    ISSN：0014-4835

  70. Choroidal neovascularization enhanced by Chlamydia pneumoniae via Toll-like receptor 2 in the retinal pigment epithelium. 国際誌 査読有り

    Takeshi Fujimoto, Koh-Hei Sonoda, Kuniaki Hijioka, Kohta Sato, Atsunobu Takeda, Eiichi Hasegawa, Yuji Oshima, Tatsuro Ishibashi

    Investigative ophthalmology & visual science　51　(9)　4694-702　2010年9月

    DOI： 10.1167/iovs.09-4464 　

    ISSN：0146-0404

  71. Activation of mitochondrial calpain and release of apoptosis-inducing factor from mitochondria in RCS rat retinal degeneration 査読有り

    Sayuri Mizukoshi, Mitsuru Nakazawa, Kota Sato, Taku Ozaki, Tomomi Metoki, Sei-ichi Ishiguro

    EXPERIMENTAL EYE RESEARCH　91　(3)　353-361　2010年9月

    DOI： 10.1016/j.exer.2010.06.004 　

    ISSN：0014-4835

  72. Crystal deposits on the lens capsules in Bietti crystalline corneoretinal dystrophy associated with a mutation in the CYP4V2 gene 査読有り

    Yumiko Yokoi, Mitsuru Nakazawa, Sayuri Mizukoshi, Kota Sato, Tomoaki Usui, Kimio Takeuchi

    ACTA OPHTHALMOLOGICA　88　(5)　607-609　2010年8月

    DOI： 10.1111/j.1755-3768.2009.01529.x 　

    ISSN：1755-375X

  73. S-opsin protein is incompletely modified during N-glycan processing in Rpe65(-/-) mice 査読有り

    Kota Sato, Mitsuru Nakazawa, Kimio Takeuchi, Sayuri Mizukoshi, Sei-ichi Ishiguro

    EXPERIMENTAL EYE RESEARCH　91　(1)　54-62　2010年7月

    DOI： 10.1016/j.exer.2010.03.020 　

    ISSN：0014-4835

  74. TEM7 (PLXDC1) in neovascular endothelial cells of fibrovascular membranes from patients with proliferative diabetic retinopathy. 査読有り

    Yamaji Y, Yoshida S, Ishikawa K, Sengoku A, Sato K, Yoshida A, Kuwahara R, Ohuchida K, Oki E, Enaida H, Fujisawa K, Kono T, Ishibashi T

    Investigative ophthalmology & visual science　49　(7)　3151-3157　2008年7月

    DOI： 10.1167/iovs.07-1249 　

    ISSN：0146-0404

︎全件表示 ︎最初の5件までを表示

MISC 70

  1. Two cases of primary open-angle glaucoma with a rare variant of the MYOC gene

    Reimi Soma, Kazuki Hashimoto, Kota Sato, Toru Nakazawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　65　(7)　2024年6月

    ISSN： 0146-0404

    eISSN： 1552-5783

  2. Uric acid -driven NLRP3 inflammasome activation triggers lens epithelial cell senescence and cataract formation

    Hongliang Lin, Yongjie Qin, Kota Sato, Toru Nakazawa, Hongyang Zhang

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　65　(7)　2024年6月

    ISSN： 0146-0404

    eISSN： 1552-5783

  3. 基礎研究コラム〈91〉マイクログリアと網膜神経節細胞死

    佐藤孝太

    あたらしい眼科　41　(12)　2024年

    ISSN： 0910-1810

  4. ヒト前房水の細胞外小胞由来リピドームを標的とした緑内障早期診断マーカー探索

    西原詩織, 佐藤孝太, 藤岡周, 横山悠, 福内友子, 山岡法子, 中澤徹, 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

  5. 視神経挫滅マウスに対するヘキソキナーゼ2の神経保護効果

    佐藤孝太, 大石路子, 林宏亮, 中澤徹

    日本眼科学会雑誌　128　2024年

    ISSN： 0029-0203

  6. 緑内障関連自己抗体による緑内障の診断機械学習モデルの確立

    石川誠, 高田菜生子, 二宮高洋, 國方彦志, 羽入田明子, 福田枝里子, 山口圭, 小野千紘, 桐原朋子, 新谷千栄, 佐藤孝太, 五島直樹, 中澤徹

    日本眼科学会雑誌　128　2024年

    ISSN： 0029-0203

  7. ラットex vivo急性緑内障モデルによるミクログリアを介したNLRP3介在型炎症反応の検討

    佐藤大夢, 石川誠, 大石路子, 神位りえ子, 佐藤孝太, 俵山寛司, 中澤徹

    日本眼科学会雑誌　128　2024年

    ISSN： 0029-0203

  8. CDKN2B-AS1遺伝子変異における培養神経細胞株への生存率の影響

    佐藤 孝太, 大石 路子, 菅野 聖世, 鄒 名愛, 河野 ちひろ, 石川 誠, 中澤 徹

    日本緑内障学会抄録集　34回　109-109　2023年9月

    出版者・発行元： 日本緑内障学会

  9. ラットex vivo緑内障モデルにおけるCSF1受容体阻害薬によるNLRP3介在型炎症反応抑制の検討

    佐藤 大夢, 石川 誠, 大石 路子, 神位 りえ子, 佐藤 孝太, 中澤 徹

    日本緑内障学会抄録集　34回　110-110　2023年9月

    出版者・発行元： 日本緑内障学会

  10. 血漿プロテオーム解析による緑内障自己抗体の同定

    高田 菜生子, 石川 誠, 佐藤 孝太, 國方 彦志, 福田 枝里子, 山口 圭, 小野 千紘, 桐原 朋子, 新谷 千栄, 五島 直樹, 中澤 徹

    日本緑内障学会抄録集　34回　110-110　2023年9月

    出版者・発行元： 日本緑内障学会

  11. 「多施設眼科バイオバンク」による眼疾患患者を対象とした検体収集の研究デザインとその進捗報告

    横山 悠, 佐藤 孝太, 橋本 和軌, 高橋 直樹, 佐藤 正隆, 高田 菜生子, 中澤 徹

    日本緑内障学会抄録集　34回　223-223　2023年9月

    出版者・発行元： 日本緑内障学会

  12. GPR84はTNF-IL-1を高発現する網膜マイクログリアのマーカーである

    佐藤 孝太, 大石 路子, 中澤 徹

    日本眼科学会雑誌　127　(臨増)　193-193　2023年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  13. ラットex vivo緑内障モデルにおける眼圧上昇時のNLRP3介在型炎症反応の誘導

    佐藤 大夢, 石川 誠, 大石 路子, 神位 りえ子, 佐藤 孝太, 中澤 徹

    日本眼科学会雑誌　127　(臨増)　193-193　2023年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  14. ウサギ眼における、ブリモニジン/ブリンゾラミド配合点眼剤の眼血流への影響について

    高橋 成奈, 佐藤 孝太, 清田 直樹, 中澤 徹

    日本眼科学会雑誌　127　(臨増)　216-216　2023年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  15. カルニチンアセチルトランスフェラーゼの過剰発現による神経保護効果の検討

    佐藤 孝太, 藤岡 周, Dong Xiaoxuan, 前川 重人, 中澤 徹

    日本緑内障学会抄録集　33回　81-81　2022年9月

    出版者・発行元： 日本緑内障学会

  16. ラットex vivo緑内障モデルにおける眼圧上昇時の網膜ミクログリアの変化

    佐藤 大夢, 石川 誠, 大石 路子, 神位 りえ子, 佐藤 孝太, 中澤 徹

    日本緑内障学会抄録集　33回　83-83　2022年9月

    出版者・発行元： 日本緑内障学会

  17. エクオール産生能と緑内障との検討

    内田 惠子, 檜森 紀子, 永井 雅, 二宮 高洋, 矢花 武史, 前川 重人, 津田 聡, 面高 宗子, 横山 悠, 佐藤 孝太, 中澤 徹

    日本緑内障学会抄録集　33回　90-90　2022年9月

    出版者・発行元： 日本緑内障学会

  18. ラット緑内障モデルにおけるNMDAチャンネル透過型プローブAGBによる神経保護メカニズムの検討

    石川 誠, 佐藤 大夢, 大石 路子, 神位 りえ子, 佐藤 孝太, 中澤 徹

    日本緑内障学会抄録集　33回　180-180　2022年9月

    出版者・発行元： 日本緑内障学会

  19. 網膜興奮毒性に対する小胞体ストレス抑制と抗炎症の相乗的な神経保護治療

    佐藤 孝太, 佐藤 大夢, 大石 路子, 中澤 徹

    日本眼科学会雑誌　126　(臨増)　251-251　2022年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  20. ラット緑内障モデルにおける神経ステロイド光学異性体の神経保護作用

    石川 誠, 佐藤 大夢, 佐藤 孝太, 國方 彦志, 吉冨 健志, 中澤 徹

    日本眼科学会雑誌　126　(臨増)　252-252　2022年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  21. UHPLC-FTMSによるヒト前房水を用いた緑内障バイオマーカー探索研究

    小暮瑞穂, 佐藤孝太, 藤岡周, 國分太貴, 吉田真彰, 横山悠, 福内友子, 山岡法子, 中澤徹, 三枝大輔, 三枝大輔

    質量分析総合討論会講演要旨集　70th　2022年

  22. LSS欠損症における組織特異的モデルマウスを用いた代謝および病理プロファイル

    和田 陽一, 菊池 敦生, 加賀 元宗, 清水 直紀, 伊藤 隼哉, 新堀 哲也, 佐藤 孝太, 中澤 徹, 中山 啓子, 青木 洋子, 仲川 清隆, 呉 繁夫

    日本先天代謝異常学会雑誌　37　126-126　2021年9月

    出版者・発行元： (一社)日本先天代謝異常学会

    ISSN： 0912-0122

  23. 正常眼圧緑内障における血中エンドセリン濃度とFlammer症候群および視野進行の関連

    高橋 成奈, 佐藤 孝太, 高田 菜生子, 志賀 由己浩, 清田 直樹, 安田 正幸, 津田 聡, 面高 宗子, 中澤 徹

    日本緑内障学会抄録集　32回　80-80　2021年9月

    出版者・発行元： 日本緑内障学会

  24. メタボローム解析による視神経障害バイオマーカーの探索

    佐藤 孝太, 三枝 大輔, 藤岡 周, 中澤 徹

    日本緑内障学会抄録集　32回　89-89　2021年9月

    出版者・発行元： 日本緑内障学会

  25. ラット緑内障モデルにおける神経ステロイドの相加的神経保護

    石川 誠, 佐藤 大夢, 佐藤 孝太, 吉冨 健志, 中澤 徹

    日本緑内障学会抄録集　32回　176-176　2021年9月

    出版者・発行元： 日本緑内障学会

  26. LSS欠損症における組織特異的モデルマウスを用いた代謝および病理プロファイル

    和田 陽一, 菊池 敦生, 加賀 元宗, 清水 直紀, 伊藤 隼哉, 新堀 哲也, 佐藤 孝太, 中澤 徹, 中山 啓子, 青木 洋子, 仲川 清隆, 呉 繁夫

    日本先天代謝異常学会雑誌　37　126-126　2021年9月

    出版者・発行元： (一社)日本先天代謝異常学会

    ISSN： 0912-0122

  27. 正常眼圧緑内障における血中エンドセリン濃度とFlammer症候群および視野進行の関連

    高橋 成奈, 佐藤 孝太, 高田 菜生子, 志賀 由己浩, 清田 直樹, 安田 正幸, 津田 聡, 面高 宗子, 中澤 徹

    日本緑内障学会抄録集　32回　80-80　2021年9月

    出版者・発行元： 日本緑内障学会

  28. メタボローム解析による視神経障害バイオマーカーの探索

    佐藤 孝太, 三枝 大輔, 藤岡 周, 中澤 徹

    日本緑内障学会抄録集　32回　89-89　2021年9月

    出版者・発行元： 日本緑内障学会

  29. ラット緑内障モデルにおける神経ステロイドの相加的神経保護

    石川 誠, 佐藤 大夢, 佐藤 孝太, 吉冨 健志, 中澤 徹

    日本緑内障学会抄録集　32回　176-176　2021年9月

    出版者・発行元： 日本緑内障学会

  30. 眼科疾患に対する創薬・再生医療研究 モデル動物を用いた網膜神経節細胞死の病態解明と創薬研究

    佐藤 孝太, 中澤 徹

    日本眼薬理学会プログラム・抄録集　40回　30-30　2021年2月

    出版者・発行元： 日本眼薬理学会

  31. 眼科疾患に対する創薬・再生医療研究 モデル動物を用いた網膜神経節細胞死の病態解明と創薬研究

    佐藤 孝太, 中澤 徹

    日本眼薬理学会プログラム・抄録集　40回　30-30　2021年2月

    出版者・発行元： 日本眼薬理学会

  32. 視神経挫滅マウス網膜のマイクログリア活性化におけるrhoキナーゼの関与

    佐藤孝太, 大石路子, 吉田真彰, 前川重人, 中澤徹

    日本眼科学会雑誌　125　2021年

    ISSN： 0029-0203

  33. 基礎研究にみる網膜神経節細胞死のメカニズム 代謝変動と網膜神経節細胞死

    佐藤 孝太, 中澤 徹

    日本緑内障学会抄録集　31回　61-61　2020年10月

    出版者・発行元： 日本緑内障学会

  34. ミトコンドリアComplex I阻害時のマウスミュラー細胞における神経栄養因子の検討

    柳町 真希, 檜森 紀子, 俵山 寛司, 佐藤 孝太, 行方 和彦, 原田 高幸, 山本 雅之, 中澤 徹

    日本緑内障学会抄録集　31回　72-72　2020年10月

    出版者・発行元： 日本緑内障学会

  35. 培養神経細胞におけるセレノネインの神経保護効果

    吉田 真彰, 佐藤 孝太, 大石 路子, 市川 惠一, 原 精一, 五味 恵子, 伊藤 考太郎, 中澤 徹

    日本緑内障学会抄録集　31回　72-72　2020年10月

    出版者・発行元： 日本緑内障学会

  36. 視神経挫滅マウス網膜における活性化マイクログリアのサイトカイン発現

    佐藤 孝太, 横山 悠, 檜森 紀子, 面高 宗子, 前川 重人, 中澤 徹

    日本緑内障学会抄録集　31回　73-73　2020年10月

    出版者・発行元： 日本緑内障学会

  37. 家兎濾過手術モデルでの偏光OCTの瘢痕定量評価と組織学的所見の関連性

    國分 太貴, 津田 聡, 浅野 俊文, 鈴木 哲章, 前川 重人, 横山 悠, 佐藤 孝太, 中澤 徹

    日本眼科学会雑誌　124　(臨増)　214-214　2020年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  38. 網膜興奮毒性障害におけるマイクログリアの活性化とヘスペリジンによる抑制効果

    前川 重人, 佐藤 孝太, 佐藤 大夢, 中澤 徹

    日本眼科学会雑誌　124　(臨増)　237-237　2020年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  39. CRISPR/Cas9によるCrat遺伝子ノックアウト細胞標識ツールの開発

    佐藤 孝太, 片山 翔太, 中澤 徹

    日本眼科学会雑誌　124　(臨増)　293-293　2020年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  40. ウサギ模擬白内障手術を用いたグルタチオン三硫化物(GS3G)による眼組織保護効果の検討

    鈴木 哲章, 國方 彦志, 俵山 寛司, 佐藤 孝太, 津田 聡, 中澤 徹

    日本眼科学会雑誌　124　(臨増)　183-183　2020年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  41. 家兎濾過手術モデルでの偏光OCTの瘢痕定量評価と組織学的所見の関連性

    國分 太貴, 津田 聡, 浅野 俊文, 鈴木 哲章, 前川 重人, 横山 悠, 佐藤 孝太, 中澤 徹

    日本眼科学会雑誌　124　(臨増)　214-214　2020年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  42. 開放隅角緑内障患者の前房水メタボローム解析

    横山 悠, 佐藤 孝太, 三枝 大輔, 藤岡 周, 國分 太貴, 前川 重人, 津田 聡, 面高 宗子, 中澤 徹

    日本眼科学会雑誌　124　(臨増)　238-238　2020年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  43. Prediction of glaucomatous visual field progression by genetic variants associated with primary open-angle glaucoma

    Fumihiko Mabuchi, Yoichi Sakurada, Kenji Kashiwagi, Mitsuko Takamoto, Makoto Aihara, Takeshi Iwata, Kazuki Hashimoto, Kota Sato, Yukihiro Shiga, Koji Nishiguchi, Toru Nakazawa, Masato Akiyama, Kazuhide Kawase, Mineo Ozaki, Makoto Araie

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　60　(9)　2019年7月

    ISSN： 0146-0404

    eISSN： 1552-5783

  44. Mitomycin C併用緑内障濾過手術におけるColchicine点眼の有効性の検討

    國分 太貴, 山本 耕太郎, 赤石 貴浩, 島崎 敦, 中村 雅胤, 佐藤 孝太, 中澤 徹

    日本眼科学会雑誌　123　(臨増)　242-242　2019年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  45. 網膜神経節細胞障害によるMCP-1誘導とヘスペリジンによる抑制効果

    佐藤孝太, 藤田幸輔, 前川重人, 佐藤大夢, 中澤徹

    日本緑内障学会抄録集　30th　2019年

  46. ミトコンドリアComplex I阻害によるマウス網膜グリア細胞変化の検討

    柳町真希, 檜森紀子, 佐藤孝太, 山本雅之, 中澤徹

    日本緑内障学会抄録集　30th　2019年

  47. PDHK阻害薬は代謝異常の是正を通じて網膜虚血再灌流障害に対して保護効果を示す

    持田誠也, 持田誠也, 佐藤孝太, 中澤徹

    日本眼科学会雑誌　123　2019年

    ISSN： 0029-0203

  48. AAV2-CRISPR/Cas9システムを用いた網膜神経節細胞のゲノム編集

    佐藤孝太, 藤田幸輔, 俵山寛司, 片山翔太, 西口康二, 中澤徹

    日本眼科学会雑誌　123　2019年

    ISSN： 0029-0203

  49. 【感覚器障害の治療と研究の最前線 QOL向上とコミュニケーションのあり方を考える】先進感覚器研究コアセンターの感覚器研究プロジェクト

    國方 彦志, 佐藤 孝太, 俵山 寛司, 中澤 徹

    ファルマシア　54　(11)　1025-1029　2018年11月

    出版者・発行元： (公社)日本薬学会

    ISSN： 0014-8601

    eISSN： 2189-7026

  50. 他分野の基礎研究から学ぶ最先端研究 メタボローム解析を応用した個別化医療

    三枝 大輔, 佐藤 孝太, 齋藤 律水, 元池 育子, 中澤 徹, 山本 雅之

    日本眼科学会雑誌　122　(臨増)　30-30　2018年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  51. 緑内障濾過手術におけるDNA topoisomerase II阻害薬の有効性の検討

    國分太貴, 山本耕太郎, 赤石貴浩, 島崎敦, 中村雅胤, 佐藤孝太, 中澤徹

    日本緑内障学会抄録集　29th　2018年

  52. 開放隅角緑内障に関わる新たな遺伝子領域の同定

    志賀由己浩, 秋山雅人, 西口康二, 佐藤孝太, 三宅正裕, 山城健児, 桃沢幸秀, 鎌谷洋一郎, 久保充明, 中澤徹

    日本緑内障学会抄録集　29th　2018年

  53. タフルプロスト徐放性製剤によるラット網膜神経節細胞への神経保護効果の検討

    中川優梨花, 佐藤孝太, 面高宗子, 浅田博之, 藤井忍, 眞崎賢治, 中澤徹

    日本緑内障学会抄録集　29th　2018年

  54. chop経路阻害はヘスペリジンによる網膜神経保護作用を増強する

    佐藤孝太, 中川優梨花, 前川重人, 中澤徹

    日本眼科学会雑誌　122　2018年

    ISSN： 0029-0203

  55. NMDA誘導性網膜障害時におけるヘスペリジンの抗炎症作用

    佐藤大夢, 佐藤孝太, 前川重人, 中澤徹

    日本眼科学会雑誌　122　2018年

    ISSN： 0029-0203

  56. 視神経挫滅モデル網膜のメタボローム解析

    佐藤孝太, 三枝大輔, 元池育子, 齋藤律水, 藤岡周, 山本雅之, 中澤徹

    日本緑内障学会抄録集　29th　2018年

  57. 緑内障患者におけるミトコンドリア障害マーカーとしてのmtDNA/nDNA比と視神経乳頭組織血流の検討

    柳町真希, 檜森紀子, 佐藤孝太, 國分太貴, 浅野俊文, 志賀由己浩, 津田聡, 國方彦志, 中澤徹

    日本緑内障学会抄録集　29th　77　2018年

  58. 先進感覚器研究コアセンターの感覚器研究プロジェクト

    國方彦志, 佐藤孝太, 俵山寛司, 中澤徹

    ファルマシア(Web)　54　(11)　1025‐1029(J‐STAGE)　2018年

    DOI： 10.14894/faruawpsj.54.11_1025 　

    ISSN： 2189-7026

  59. 新規開発蛍光プローブを用いたカルパイン活性の評価

    津田聡, 津田聡, 浅野俊文, 伊藤梓, 佐藤孝太, 藤田幸輔, 國方彦志, 神谷真子, 浦野泰照, 中澤徹

    日本緑内障学会抄録集　29th　128　2018年

  60. 新規開発蛍光プローブを用いたカルパイン活性の生体内イメージング

    浅野俊文, 津田聡, 伊藤梓, 佐藤孝太, 藤田幸輔, 國方彦志, 神谷真子, 浦野泰照, 中澤徹

    日本緑内障学会抄録集　29th　127　2018年

  61. マウス緑内障モデル網膜のメタボローム解析

    佐藤 孝太, 三枝 大輔, 斉藤 律水, 中澤 徹

    日本眼科学会雑誌　121　(臨増)　186-186　2017年3月

    出版者・発行元： (公財)日本眼科学会

    ISSN： 0029-0203

  62. 複合サプリメント摂取による抗酸化力の変動

    檜森紀子, 佐藤孝太, 中澤徹

    日本緑内障学会抄録集　28th　2017年

  63. 興奮毒性障害モデルに対する食品由来素材含有サプリメントの網膜保護効果の検討

    前川重人, 前川重人, 佐藤孝太, 國分太貴, 中澤徹

    日本緑内障学会抄録集　28th　2017年

  64. Inhibition of Sp1 signaling promotes retinal ganglion cell death via apoptotic and necrotic pathways in a model of glaucoma

    Kota Sato, Yukihiro Shiga, Kazuko Omodaka, Shigeto Maekawa, Namie Murayama, Toru Nakazawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　57　(12)　2016年9月

    ISSN： 0146-0404

    eISSN： 1552-5783

  65. 網膜下線維瘢痕化におけるインターロイキン(IL)-6の関与

    長谷川英一, 佐藤孝太, 武田篤信, 大島裕司, 中澤徹, JO Young-Joon, 園田康平

    日本眼感染症学会・日本眼炎症学会・日本コンタクトレンズ学会総会・日本涙道・涙液学会プログラム・講演抄録集　53rd-50th-59th-5th　2016年

  66. In vivoイメージングによるNMDA障害後の網膜神経節細胞死の評価

    伊藤梓, 國方彦志, 前川重人, 津田聡, 佐藤孝太, 浅井信晴, 中澤徹

    日本緑内障学会抄録集　27th　89　2016年

  67. Role of GDNF receptor-related genes to axonal damage-induced retinal ganglion cell death and regeneration

    Kazuko Omodaka, Takuji Kurimoto, Orie Nakamura, Kota Sato, Masayuki Yasuda, Noriko Himori, Yu Yokoyama, Toru Nakazawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　56　(7)　2015年6月

    ISSN： 0146-0404

    eISSN： 1552-5783

  68. Preperimetric glaucoma pathophysiological study part3: Association between EDNRA genotype and the effect of a prostaglandin analogue on ocular blood flow

    Yukihiro Shiga, Nobuo Fuse, Kota Sato, Naoko Aizawa, Satoru Tsuda, Masae Kimura, Koji Nishiguchi, Tomoki Yasui, Keiichi Kato, Toru Nakazawa

    INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE　56　(7)　2015年6月

    ISSN： 0146-0404

    eISSN： 1552-5783

  69. 緑内障モデル動物における神経節細胞死とネクロプトーシス経路の関与

    佐藤孝太, 志賀由己浩, 面高宗子, 前川重人, 村山奈美枝, 中澤徹

    日本緑内障学会抄録集　26th　2015年

  70. マウス視神経挫滅モデルの網膜神経節細胞障害におけるECEL1の関与

    志賀由己浩, 佐藤孝太, 前川重人, 面高宗子, 丸山和一, 西口康二, 中澤徹

    日本緑内障学会抄録集　26th　2015年

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 16

  1. 非ヒト霊長類を用いた眼血流不全による正常眼圧緑内障の病態解明

    佐藤 孝太, 三枝 大輔

    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

    2025年4月1日 ～ 2028年3月31日

  2. ヒト緑内障GWASからの個別化創薬プラットフォーム構築研究

    中澤 徹, 石川 誠, 佐藤 孝太, 杉江 淳, 津田 聡, 大石 路子

    2024年4月1日 ～ 2027年3月31日

  3. STING経路に着目した滲出型加齢黄斑変性の網膜下線維化の病態解明

    安田 正幸, 俵山 寛司, 佐藤 孝太

    2023年4月1日 ～ 2026年3月31日

  4. マーモセットを用いた緑内障関連遺伝子の病態解明

    佐藤 孝太

    2022年4月1日 ～ 2025年3月31日

  5. 疾患関連マイクログリアクラスター制御による視神経保護治療

    大石 路子, 佐藤 孝太, 中澤 徹

    2022年4月1日 ～ 2025年3月31日

  6. 眼圧上昇時のミクログリア起因性炎症反応の制御による神経保護の可能性

    石川 誠, 佐藤 孝太

    2022年4月1日 ～ 2025年3月31日

  7. 瘢痕化定量技術と薬剤ナノ粒子化による組織移行性の高い濾過胞瘢痕抑制薬の開発

    津田 聡, 中澤 徹, 笠井 均, 小関 良卓, 佐藤 孝太, 國分 太貴

    2021年4月1日 ～ 2024年3月31日

  8. 前眼部組織間のトランスオミクス解析による包括的な眼圧上昇機序の解明

    横山 悠, 中澤 徹, 國分 太貴, 矢花 武史, 佐藤 孝太, 津田 聡, 前川 重人, 三枝 大輔

    2021年4月1日 ～ 2024年3月31日

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    本研究は緑内障病態理解のため、眼科的臨床データと前房水と線維柱帯のメタボローム解析、プロテオーム解析等を用いた包括的な関連解析を行う研究である。本年度はおもに線維柱帯切開術を行うことを予定された広義原発開放隅角緑内障を対象にサンプル採取を行う計画であった。患者に研究計画を説明し同意を書面上で取得した。手術のための末梢ライン確保時に採血、また同日に検尿を行った上でKahook dual bladeを用いた線維柱帯採取を試みた。しかし、Kahook Dual bladeは新しい型へと変更しており、よりBlade部が小さく改良された。そのため検体採取が手技的に難しくなり、何例がで採取を試みたが検体を得られなかった。現在は旧タイプのKahook Dual bladeの入手は困難となったため、25ゲージ硝子体手術用鑷子、さらにはまだ試用中であったTrabEx+(TM)を用いた線維柱帯採取を試みたが採取部位が非常に小さいこと、出血による視認困難などの理由により。採取できなかった。ほかには代替案として濾過手術など別術式による採取を検討している。濾過手術は虹彩も切除するためより包括的な前房内環境の解析が可能となる。しかし術中、マイトマイシンCなどの薬剤を使用するために解析に何らかの影響を及ぼすことが否定できない。引き続き線維柱帯切開術時、ケリー氏トラベクレクトミーパンチ等別の硝子体手術鑷子等の眼科手術器具を手配して検体採取を行う予定である。

  9. 統合解析を用いた網膜神経節細胞別の脆弱性に関わる緑内障障害シグナル伝達経路の探索

    面高 宗子, 岡田 眞里子, 中澤 徹, 佐藤 孝太

    2021年4月1日 ～ 2024年3月31日

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    緑内障は成人途失明原因第一位の眼疾患で、本邦は世界に類を見ないスピードで高齢化が進んでおり、今後も緑内障による失明患者数の増加が確実視されている。緑内障の本態は網膜神経節細胞（RGC）の細胞死であるが、現行の治療は眼圧を下降させる治療のみでありアンメットメディカルニーズが存在する。RGC死の詳細なメカニズムを明らかにして、治療薬の開発に繋げていく必要がある。これまでも、げっ歯類を用いた創薬研究は90％以上開発段階で中止となっており、ヒト緑内障の病態を意識した開発が不可欠となる。緑内障では太い軸索を有する大きなRGCが早期から障害され、小さなRGCはミトコンドリア障害に脆弱であることが知られている。本研究では多因子疾患である緑内障のシンプルな障害モデルを作成し、基礎研究技術の進歩を駆使し、緑内障動物モデルにより、げっ歯類RGCをセルソータでサイズ別に分取し、網羅的遺伝子発現解析とメタボローム解析の統合解析から、大小RGCの細胞死シグナルメカニズムを探索する。 「動物モデルから統合解析によるプロファイルデータ取得にむけて」 マウス障害モデルについて、軸索挫滅・眼圧上昇・酸化ストレス障害モデルに対し、上丘からフルオロゴールド逆行性染色、およびフラットマウントRBPMS抗体免疫染色法により、障害モデルにおける継時的な細胞数の評価を行った。網羅解析に有用な時期は、細胞密度減少の直前とされていることから、それぞれの障害モデルにおいて、サンプル回収に適した時期の同定を行った。続いて、マウス網膜をパパイン酵素処理し、神経細胞を単離し、Thy1.2抗体によりRGCをラベル、細胞サイズでゲートをかけ、セルソータによるRGCの細胞サイズによるカウントと分取を行った。障害後の複数のタイムポイントで、生存するRGCをサイズ別に検討し、障害の種類により、RGCの大小で脆弱性が異なることを検討した。

  10. ヒトiPS細胞由来網膜神経節細胞と人工篩状板移植による網膜視神経再生

    中澤 徹, 小林 航, 佐藤 孝太, Sharma Parmanand

    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 Challenging Research (Exploratory)

    研究機関：Tohoku University

    2021年7月9日 ～ 2023年3月31日

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    本研究では難治性視神経疾患に対する新しい治療法としてヒトiPS細胞由来網膜神経節細胞移植の基盤を構築することが目的である。本年度はヒトiPS細胞由来網膜神経節細胞がマウスの網膜にどの程度生着するかの検討を行った。ヒトiPS細胞由来網膜神経節細胞は透明でありマウスの網膜に生着したとしてもライブイメージングで観察することが困難なため、Crispr/cas9のゲノム編集技術を利用して網膜神経節細胞の特異的マーカーであるPou4f2遺伝子をGFPで蛍光標識したiPS細胞株を使用した。このiPS細胞から分化誘導した3次元人工的立体網膜組織において、網膜神経節細胞マーカーによる免疫染色でＧＦＰと共染色されることを確認し、GFP蛍光を認めた細胞が網膜神経節細胞であることを確認した。分化誘導した立体網膜組織から単離したヒトiPS細胞由来網膜神経節細胞を8週齢のC57BL/6マウス5匹の硝子体内へ細胞注射を施行した。マウス用眼底観察装置Micronを用いて注射後1週間に眼底を観察したところ全てのマウス眼底に明らかな蛍光発現を認めず、1匹では水晶体後面にわずかに蛍光発現を認めていた。この結果から浮遊細胞では硝子体中で浮き上がり生着が難しいことが原因と考えられた。そこで、同様に8週齢のC57BL/6マウスの網膜を摘出し、Explant cultureを行ってこの上に単離したヒトiPS細胞由来網膜神経節細胞を播種した。3日後の観察で蛍光を有する神経突起が観察され、網膜上に生着すれば神経突起伸長が得られることが示唆された。

  11. CRISPRスクリーニングによる緑内障感受性遺伝子の同定

    中澤 徹, 小林 航, 佐藤 孝太

    2020年4月1日 ～ 2023年3月31日

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    緑内障は本邦の中途失明原因第一位の眼疾患である。病態は多因子疾患であるにも関わらず、眼圧下降治療しか存在せず、眼圧下降治療後も視野欠損が進行する症例が40％認め、アンメットメデ ィカルニーズが存在する。そのため、緑内障の眼圧以外の病態を明らかにし、病態特異的治療の開発が急務である。緑内障には遺伝的要因があり、ゲノムワイド関連解析（GWAS）により複数の緑内障関連SNPが同定されている。しかし、病態との因果関係について十分に検討されていない。そのため本研究では、神経保護治療のターゲットとなる網膜神経節細胞の脆弱性に寄与する遺伝子変異とそのメカニズムを同定することを目的とした。本年度は、臨床パラメータとSNP情報を関連解析するための検査データセットを構築した。また、GWASにより同定されたゲノムワイド有意水準を超えるSNPならびにその近傍にある遺伝子について調査し、CRISPRスクリーニングの対象とする遺伝子について精査した。加えて、近年報告された国際コンソーシアムによる緑内障GWASから計算されたpolygenic risk scoreの利用を念頭においた解析準備を進めた。基礎研究では、緑内障関連遺伝子の表現型を評価するための細胞株を選定し、細胞培養条件や緑内障病態を反映するストレス負荷条件（酸化ストレス、興奮毒性、炎症、低栄養、低酸素）について検討した。

  12. 統合オミックス解析による視神経障害モデルマウスの病態機構解明

    佐藤 孝太

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

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

    研究機関：Tohoku University

    2019年4月1日 ～ 2022年3月31日

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    本研究では、生体内の代謝産物およびmRNAの網羅解析をおこない、その結果を包括的に解釈する統合オミックス解析をおこなうことで、視神経障害における網膜神経節細胞の代謝異常のダイナミズムを予測し、緑内障モデル動物において網膜神経節細胞死との関連が報告されているNrf2の活性低下を調べることを目的とした。RNA-seqの結果、Nrf2発現や下流のNqo1の発現低下は認められなかった。一方で、グルコースの低下や解糖系に関連する遺伝子群の発現減少が生じており、視神経挫滅時における網膜神経節細胞内での解糖系の減衰によるエネルギー産生低下が示唆された。

  13. メタボロミクスによる緑内障モデルマウスの病態解明

    佐藤 孝太

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

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

    研究機関：Tohoku University

    2017年4月1日 ～ 2019年3月31日

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    緑内障における網膜神経節細胞死の一つの側面を反映する動物モデルとされている、視神経挫滅処置をマウスにおこない、その経時的な代謝物の変動をLC-FTMS およびUPLC-QTOF/MSにより解析した。網膜神経節細胞障害の初期、中期および後期において減少および増加する代謝群を同定した。その変動パターンのからヒートマップを作成し、クラスター解析により、４つの特徴的な代謝物変動群が存在することを明らかにした。 また、その代謝物の局在をイメージングMSを用いて検討した。その結果、疾患モデル群で変動の見られたいくつかの代謝物は、網膜神経節細胞が限局するGCLにおいて特に大きな変動を示したことを明らかにした。

  14. 神経活動依存的プロモーターを用いた網膜神経節細胞機能のイメージング法の確立

    中澤 徹, 西口 康二, 藤田 幸輔, 佐藤 孝太, 横山 悠, 村山 奈美枝

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research

    研究種目：Grant-in-Aid for Challenging Exploratory Research

    研究機関：Tohoku University

    2016年4月1日 ～ 2018年3月31日

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    緑内障等の多くの眼疾患で網膜神経節細胞（RGC）障害により不可逆的視機能の損失を来す。病態解明のため、RGC機能を高い精度で評価するin vivo実験系の確立を目指した。神経活動依存性に活性化されるE-SAREの下流に蛍光タンパク質遺伝子を組み込んだAAVベクターを作製し、マウスに投与後、暗順応と光暴露を行い、共焦点走査型レーザー検眼鏡で観察、定量した。光暴露後2時間でin vivoで光応答するRGCが可視化された。一方、光暴露後2時間の暗順応で陽性細胞が45％減少した。E-SAREとAAVを組み合わせることにより、光応答するGCをin vivoで可視化する事に成功した。

  15. 緑内障モデル動物におけるEcel1の機能解析と治療への応用

    佐藤 孝太

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

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

    研究機関：Tohoku University

    2015年4月1日 ～ 2017年3月31日

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    緑内障モデルマウスの網膜内で発現上昇するEcel1の発現機序および機能解析を目的とした。qPCR、ウェスタンブロッティングおよび免疫染色の結果から、視神経挫滅により網膜神経節細胞障害を誘導したところ、視神経挫滅４日後にEcel1が網膜神経節細胞に高発現することを確認した。また、Ecel1はNMDA障害では誘導されないが、軸索流障害によって軸索挫滅と同程度に高発現を示した。網膜神経節細胞にEcel1を高発現するAAV2-mEcel1ウイルスベクターを作成した。このウイルスを眼内に投与し視神経挫滅を行ったところ、仮説とは異なり、Ecel1高発現群での神経保護効果は認められなかった。

  16. 緑内障モデルマウスを用いた神経節細胞障害におけるネクロプトーシス細胞死経路の解析

    佐藤 孝太

    提供機関：Japan Society for the Promotion of Science

    制度名：Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity start-up

    研究種目：Grant-in-Aid for Research Activity start-up

    研究機関：Tohoku University

    2014年8月29日 ～ 2015年3月31日

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    マウス視神経挫滅をおこなうことにより緑内障モデルを作製した。視神経経挫の２日後、４日後、７日後に網膜を摘出し、リアルタイムPCR法により神経節細胞特異的に発現するマーカー遺伝子群（Thy1, Nefh, Brn3a, Brn3b, Brn3c）の発現量を調べた。上記マーカー遺伝子群の発現量は視神経挫滅後に経時的に減少しており、神経節細胞の障害に伴う緑内障モデル動物の作製に成功していることを確認した。フルオロゴールドを用いた逆行性染色による生存ガングリオン細胞数の計測の結果からも、視神経挫滅により神経節細胞死が誘導されていることを確認した。また、近年新たに神経節細胞マーカーとして報告されたRbpmsの遺伝子発現、タンパク質発現および局在を視神経挫滅後の網膜において調べたところ、既報のマーカーに比べて定量性および再現性良く緑内障モデルの進行を評価できることを明らかにした。加えて、マウス視神経挫滅時の網膜において、ネクロプトーシス細胞死に関わる因子であるTNFα, TNF受容体, RIP1, RIP3の遺伝子発現をリアルタイムPCRにより調べた。その結果、視神経挫滅後のマウス網膜においてこれらの遺伝子発現が上昇しており、そのピークが視神経挫滅４日後であることを明らかにした。さらに、TNF受容体, RIP1, RIP3のタンパク質発現をウエスタンブロッティングにより調べたところ、リアルタイムPCRの結果に一致して TNF受容体, RIP1, RIP3のタンパク質発現が視神経挫滅４日後をピークとして上昇していることを明らかにした。

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