三浦 綾子 (ミウラ アヤコ)

MIURA Ayako

写真a

所属

医学部 医学科 機能制御学講座薬理学分野

職名

助教

外部リンク

学位 【 表示 / 非表示

  • 博士(医学) ( 2013年3月   鹿児島大学 )

研究分野 【 表示 / 非表示

  • ライフサイエンス / 呼吸器内科学

 

論文 【 表示 / 非表示

  • Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome. 査読あり

    Matsuo A, Tanida R, Yanagi S, Tsubouchi H, Miura A, Shigekusa T, Matsumoto N, Nakazato M

    European journal of pharmacology   892   173754   2020年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:European Journal of Pharmacology  

    © 2020 The Authors Fibrotic scarring is an important prognostic factor of acute respiratory distress syndrome (ARDS). There are currently no antifibrotic drugs or other therapeutic agents for ARDS. Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring by facilitating collagen cross-linking. Recent clinical trials revealed that a monoclonal inhibitory antibody against LOXL2 failed to show benefit over placebo in patients with fibrotic disorders involving the lungs. These clinical results raise the possibility that targeting the extracellular enzymic activity of LOXL2 is not in itself sufficient to prevent fibrotic scarring. We investigated the role of LOXL2 in the pathogenesis of ARDS in vivo, in vitro, and in samples from patients with ARDS. After lung injury, LOXL2 was unevenly expressed in the nuclei of lung fibroblasts and myofibroblasts in the fibrotic phase. Nuclear LOXL2 expression was upregulated in lung fibroblasts after transforming growth factor-beta1 (TGF-β1)-treatment. LOXL2 silencing abrogated the TGF-β1-induced expression of a myofibrogenic-progenitor marker, the appearance of proto-myofibroblasts, and the evolution of differentiated myofibroblasts in lung fibroblasts. Nuclear upregulation of Snail was evident in myofibroblasts during the fibrotic phase after lung injury. We detected high levels of LOXL2 protein in the lungs of ARDS patients, specifically during the proliferative and fibrotic phases. Our results highlight nuclear LOXL2 in fibroblasts as a primary causative driver of cell-fate decision toward myofibroblasts and of the progression of fibrotic scarring. A nuclear-LOXL2-targeted agent could be a promising therapeutic strategy against fibrotic disorders including ARDS.

    DOI: 10.1016/j.ejphar.2020.173754

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  • Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice 査読あり

    Ishii N, Tsubouchi H, Miura A, Yanagi S, Ueno H, Shiomi K, Nakazato M

    European Journal of Pharmacology   819   35 - 42   2018年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:European Journal of Pharmacology  

    © 2017 Elsevier B.V. Paclitaxel is an effective chemotherapeutic agent, but has some treatment-limiting adverse effects that markedly decrease patients’ quality of life. Peripheral neuropathy is one of these, and no treatment for it has been established yet. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is secreted from the stomach and has widespread effects on multiple systems. We investigated the pharmacological potential of ghrelin in preventing paclitaxel-induced peripheral neuropathy using wild-type mice, ghrelin-null mice, and growth hormone secretagogue receptor-null mice. In wild-type mice, ghrelin administration alleviated mechanical and thermal hypersensitivity, and partially prevented neuronal loss of small unmyelinated intraepidermal nerve fibers but not large myelinated nerve fibers. Moreover, ghrelin administration decreased plasma oxidative and nitrosative stress and increased the expression of uncoupling protein 2 (UCP2) and superoxide dismutase 2 (SOD2) in the dorsal root ganglia, which are mitochondrial antioxidant proteins, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a regulator of mitochondrial number. Both ghrelin-null mice and growth hormone secretagogue receptor-null mice developed more severe nerve injuries than wild-type mice. Our results suggest that ghrelin administration exerts a protective effect against paclitaxel-induced neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions, and that endogenous ghrelin has a neuroprotective effect that is mediated by ghrelin/growth hormone secretagogue receptor signaling. Ghrelin could be a promising therapeutic agent for the management of this intractable disease.

    DOI: 10.1016/j.ejphar.2017.11.024

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  • Neuromedin U suppresses glucose-stimulated insulin secretion in pancreatic β cells 査読あり

    Zhang W,Sakoda H,Miura A,Shimizu K,Mori K,Miyazato M,Takayama K,Hayashi Y,Nakazato M

    Biochemical and Biophysical Research Communications   493 ( 1 )   677 - 683   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochemical and Biophysical Research Communications  

    © 2017 The Authors Neuromedin U (NMU), a highly conserved peptide in mammals, is implicated in energy homeostasis and glycemic control, and may also be involved in the regulation of adipoinsular axis function. However, the role of NMU in regulating insulin secretion has not been clearly established. In this study, we investigated the role of NMU in the regulation of insulin secretion both in vitro and in vivo. We found that NMU and NMU receptor (NMUR) 1 were expressed in mouse islets and β cell-derived MIN6-K8 cells. In mice, NMU suppressed glucose-stimulated insulin secretion (GSIS) both in vitro and in vivo. Additionally, an NMUR1 agonist inhibited GSIS in both MIN6-K8 cells and mice islets. Moreover, NMU attenuated intracellular Ca2+ influx in MIN6-K8 cells, potentially causing a decrease in insulin secretion. siNmu-transfected MIN6-K8 cells showed elevated GSIS. Treatment with anti-NMU IgG increased GSIS in isolated mouse pancreatic islets. These results suggested that NMU can act directly on β cells through NMUR1 in an autocrine or paracrine fashion to suppress insulin secretion. Collectively, our results highlight the crucial role of NMU in suppressing pancreatic insulin secretion, and may improve our understanding of glucose homeostasis.

    DOI: 10.1016/j.bbrc.2017.08.132

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  • Conformational change in the ligand-binding pocket via a KISS1R mutation (P147L) leads to isolated gonadotropin- releasing hormone deficiency 査読あり

    Shimizu K., Yonekawa T., Yoshida M., Miyazato M., Miura A., Sakoda H., Yamaguchi H., Nakazato M.

    Journal of the Endocrine Society   1 ( 10 )   1259 - 1271   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of the Endocrine Society  

    © 2017 Endocrine Society. Context: Kisspeptin receptor (KISS1R) is expressed in hypothalamic gonadotropin-releasing hormone neurons and responsible for pubertal onset and reproductive functions. KISS1R mutations remain a rare cause of congenital hypogonadotropic hypogonadism (CHH). Objective: The aim of this study was to identify the genetic cause ofCHHin a patient and to functionally characterize a KISS1R mutation. Design: The patient was a 47-year-old Japanese man whose parents were first cousins. He lacked secondary sexual characteristics owing to normosmic CHH. Exon segments for the KISS1R gene in this patient were screened for mutations. Functional analyses were performed using HEK293 cells expressing KISS1R mutants. Molecular dynamics simulations were performed to compare the ligand- KISS1R mutant complex with those of wild-type KISS1R variants. Results: A homozygous mutation (c.440C > T, p.P147L) in KISS1R was identified. The P147L mutation did not affect either receptor expression level or subcellular localization in the recombinant expression system. Intracellular calcium measurements and cellular dielectric spectroscopy demonstrated that the P147L mutation impaired receptor function to an extent more severe than that of a previously reported L148S mutation. A receptor-ligand binding assay showed the P147L mutation causes a substantial loss of ligand-binding affinity. Molecular dynamics simulations revealed the P147L mutation decreases the contact surface area of the ligand-receptor complex in an expanded ligand-binding pocket. Conclusion: We identified a loss-of-function mutation in KISS1R associated with CHH. Our results demonstrated that the P147L mutation causes a severe phenotype and functional impairment resulting from the loss of ligand-binding affinity due to an expanded ligand-binding pocket.

    DOI: 10.1210/js.2017-00277

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  • Ghrelin does not influence cancer progression in a lung adenocarcinoma cell line 査読あり

    Tsubouchi H, Onomura H, Saito Y, Yanagi S, Miura A, Matsuo A, Matsumoto N, Nakazato M

    Endocrine Journal   64 ( Suppl. )   S41 - S46   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Endocrine Journal  

    © 2017 The Japan Endocrine Society. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced in the human stomach. Although ghrelin has therapeutic potential for cancer cachexia, ghrelin treatment may have a concern about accelerating cancer progression. Here, using the human lung adenocarcinoma cell line HLC-1, we investigated the effects of ghrelin on molecular mechanisms linked to cancer progression, including cell viability, proliferation, resistance to apoptosis, and mitochondrial activity. Both types of mouse alveolar epithelial cells (types I and II) expressed the GHSR, as did the human normal airway cell lines BEAS-2B and HLC-1. Treatment with ghrelin (10−2, 10−1, 1, 10 μM) did not affect cell viability or proliferation. Pretreatment of HLC-1 cells with ghrelin (10 μM) did not affect resistance to paclitaxel-induced apoptosis. The parameters of mitochondrial respiration, including basal respiration, proton leak, ATP production, maximal respiration, spare respiratory capacity, and non-mitochondrial respiration, of the HLC-1 cells pretreated with or without ghrelin were unchanged. Taken together, ghrelin does not influence cancer progression in lung adenocarcinoma cells.

    DOI: 10.1507/endocrj.64.S41

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受賞 【 表示 / 非表示

  • ERS Young Scientist Sponsorship

    2016年9月   Europian Respiratory Society   The role of Pten in the cell-fate determination of epithelial cells in lung development.

    三浦綾子

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    受賞区分:国際学会・会議・シンポジウム等の賞  受賞国:グレートブリテン・北アイルランド連合王国(英国)

  • Kyushu Diabetes Research Conference 最優秀奨励賞

    2016年7月   Kyusyu Diabetes Research Conference   糖代謝調節に機能する新規生理活性ペプチドの発見

    三浦綾子

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    受賞区分:国内学会・会議・シンポジウム等の賞  受賞国:日本国

  • 児玉記念基礎医学助成基金 優秀研究論文顕彰

    2013年10月   児玉記念基礎医学助成基金   Pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC1) gene is suppressed by transglutaminase 2 activation.

    三浦綾子

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    受賞区分:出版社・新聞社・財団等の賞  受賞国:日本国

科研費(文科省・学振・厚労省)獲得実績 【 表示 / 非表示

  • 異種細胞間の細胞接着装置の恒常性維持機構の解析

    研究課題/領域番号:21K08183  2021年04月 - 2024年03月

    科学研究費補助金   基盤研究(C)

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    担当区分:研究代表者 

  • 肺発生時の上皮細胞運命制御とプログラムされた細胞老化におけるPtenの役割

    研究課題/領域番号:17K16051  2017年04月 - 2021年03月

    科学研究費補助金  若手研究(B)

  • 上皮間葉連関を焦点とした肺発生での上皮Ptenの機能解析

    研究課題/領域番号:26860610  2014年04月 - 2016年03月

    科学研究費補助金  若手研究(B)

その他競争的資金獲得実績 【 表示 / 非表示

  • アクチン骨格の制御因子であるフォルミン蛋白質Fhood1の腎糸球体上皮細胞(ポドサイト)における濾過機能に及ぼす影響の検討

    2021年04月 - 2022年03月

    宮崎大学  令和3年度戦略重点経費 

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    担当区分:研究代表者 

  • 異種細胞間の細胞接着装置の恒常性維持機構の解析

    2020年04月 - 2021年03月

    宮崎大学  令和2年度戦略重点経費 

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    担当区分:研究代表者 

寄附金・講座・研究部門 【 表示 / 非表示

  • 内科学講座神経呼吸内分泌代謝学分野研究奨学金(生活習慣病)

    寄附者名称:日本応用酵素協会 2019年09月