Genetic dissection of rare MODY by multidisciplinary functional genomics
| Project/Area Number |
18H02779
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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| Research Institution | Gifu University |
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Principal Investigator |
HORIKAWA YUKIO 岐阜大学, 医学部附属病院, 准教授 (10323370)
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| Co-Investigator(Kenkyū-buntansha) |
塩谷 真由美 岐阜大学, 医学部附属病院, 講師 (10293565)
飯塚 勝美 岐阜大学, 医学部附属病院, 講師 (40431712)
細道 一善 金沢大学, 医学系, 准教授 (50420948)
矢部 大介 岐阜大学, 大学院医学系研究科, 教授 (60378643)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥9,100,000 (Direct Cost: ¥7,000,000、Indirect Cost: ¥2,100,000)
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| Keywords | MODY / 原因遺伝子 / HNF / 単一遺伝子疾患 / 多因子疾患 / インスリン分泌 / 次世代シークエンサー / コピー数変異 / エンハンサー / エクソーム / in situ hybridization / 機能ゲノミクス / 遺伝子診断 / 候補遺伝子パネル / インスリン分泌不全 / 細胞骨格分子 / トランスクリプトーム / レギュローム |
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| Outline of Final Research Achievements |
The cytoskeletal molecule MYO5A was identified as a promising novel MODY candidate gene by combining linkage analysis and exosome by NGS with special reference to the islet functional network. On the other hand, the type 2 diabetes susceptibility gene, calpain 10 was subjected to analysis using an ultrasensitive mass spectrometer, and the microtubule-binding protein (MAP1B) was identified as a target substrate. Interestingly, MAP1B and MYO5A are known to be important partners in the cytoskeleton and may be coordinated in insulin secretion. In addition, a novel regulatory mechanism of glucokinase was found to be mediated by ubiquitination by cereblon, and the mechanism of low insulin secretion by arginine in MODY2 was elucidated.
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| Academic Significance and Societal Importance of the Research Achievements |
MODY1-6 遺伝子にコードされる一連のHNF転写因子ネットワークの知見は、インスリン分泌調節のみならず、膵島の発生・分化のプログラムの理解に大きく貢献した。新規MODY候補遺伝子MYO5AとMAP1Bの相互作用やグルコキナーゼ(MODY2)のアルギニンを介した新規制御機構など膵島における新たな機能プログラムの解明は、新規インスリン分泌促進薬の開発研究やその周辺因子による膵島再生や新生による糖尿病根治的治療の開発研究にも発展しうる。さらに本研究成果は、メンデル遺伝のみならず、多因子疾患である２型糖尿病にも貢献する一方、本戦略成果は他の遺伝性の希少疾患の解析モデルにもなるであろう。
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Report
(4 results)
Research Products
(42 results)
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[Journal Article] Effects of ChREBP deficiency on adrenal lipogenesis and steroidogenesis2021
Author(s)
Takao Ken、Iizuka Katsumi、Liu Yanyan、Sakurai Teruaki、Kubota Sodai、Kubota-Okamoto Saki、Imaizumi Toshinori、Takahashi Yoshihiro、Rakhat Yermek、Komori Satoko、Hirose Tokuyuki、Nonomura Kenta、Kato Takehiro、Mizuno Masami、Suwa Tetsuya、Horikawa Yukio、Sone Masakatsu、Yabe Daisuke
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Journal Title
J. Endocrinol.
Volume: 248
Pages: 317-324
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Alcohol-induced impaired insulin secretion in a Japanese population: Five-year follow-up in the Gifu Diabetes Study2020
Author(s)
Ueda N, Yamamoto M, Nakamura M, Motooka Y, Nakayama Y, Nonoyama,Y, Oba S, Horikawa Y, Nagata C, and Yabe D; Gifu Diabetes Study Group
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Journal Title
J Diabetes Investig
Volume: 11
Pages: 1207-1214
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A case of MODY5-like manifestations without mutations or deletions in coding and minimal promoter regions of the HNF1B gene.2020
Author(s)
Kuwabara-Ohmura y, Iizuka K, Liu Y, Takao K, Nonomura K, T Kato, Mizuno M, Hosomichi K, Miyazaki T, Horikawa Y, Yabe D
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Journal Title
NAID
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Periodontal disease may be associated with the occurrence of diabetic retinopathy: A subgroup analysis of the survey of the Diabetes Coordination Notebook in Gifu2020
Author(s)
Horikawa Y, Suzuki A, Enya M, Hashimoto K, Nishida S, Kobayashi R, Ohashi T, Yamazaki F, Totani R, Kobayashi H, Yamamoto M, Itoh Y and Takeda J
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Journal Title
Exp Clin Endocrinol Diabetes
Volume: -
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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