Molecular Mechanisms of the Signaling for Cystic Kidney Diseases
| Project/Area Number |
17K09719
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Kansai Medical University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 腎不全 / 腎嚢胞 / mTOR / 線毛 / 遺伝子変異 / 嚢胞腎 / ｍTOR / マウスモデル / 疾患遺伝子 / シグナル伝達 |
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| Outline of Final Research Achievements |
We studied in-house mouse model, Cd79a-Cre:Tsc1ff, recapitulating human ADPKD histology. The Cre mediated-Tsc1 depletion driven by Cd79a (mb1), the known B cell receptor, allowed conditional mTORC1 activation along the distal nephron after embryonic E16. Cysts formed from the distal nephron as early as postnatal two weeks and developed definite PKD by four weeks.
In the Cd79a-Cre:Tsc1ff tubules, epithelial cells continued to proliferate even after completing the nephrogenesis around postnatal 14 days. Elongation of cilia and disorientation of cell intercalation as well as oriented cell division were seen in pre-cystic, developing tubules. Our results indicate that PKD phenotypes arising from over-activation of mTORC1 in developing distal nephron closely resemble to those of the primary cilia disorder ADPKD. Cystogenesis are likely triggered during developmental stage of tubulogenesis, when the optimal tubule diameter has been shaped through coordinated proliferation with polarity.
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| Academic Significance and Societal Importance of the Research Achievements |
①難病の病態解明と治療シーズ探索 本研究で確立したADPKDモデルマウスを用いて嚢胞形成の鍵を握る標的分子を探索することにより、根本的に嚢胞形成を抑止しうる新たな治療薬の開発に貢献できる。
②学術的意義: 嚢胞形成は発達段階の尿細管上皮が有する多彩な分化機能(増殖、分裂、極性、アポトーシス、細胞間接着等)の統合的な機能制御不全であり、病態解明は器官形成という生命現象と、それが破綻した疾患病態の理解に役立つ。③社会貢献:ADPKDは最も頻度の高い遺伝性腎疾患で、透析原因の5-10%を占めている。本症のモデルマウスを活用する病態解明と治療開発は、社会経済的に医療費抑止の観点からも重要となる。
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Report
(7 results)
Research Products
(52 results)
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[Journal Article] A Nationwide Survey on Danon Disease in Japan2018
Author(s)
Sugie Kazuma、Komaki Hirofumi、Eura Nobuyuki、Shiota Tomo、Onoue Kenji、Tsukaguchi Hiroyasu、Minami Narihiro、Ogawa Megumu、Kiriyama Takao、Kataoka Hiroshi、Saito Yoshihiko、Nonaka Ikuya、Nishino Ichizo
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Journal Title
International Journal of Molecular Sciences
Volume: 19
Issue: 11
Pages: 3507-3507
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Genetic Screening of the Childhood and Adolescence-onset of Steroid Resistant Nephrotic Syndrome2023
Author(s)
TN Truc Linh, Ueda H, TT Houng, Tsuji S, Sato C, Hashiyada M, Sugimoto K, Hattori M, Nozu K, Tsukaguchi H.
Organizer
World Congress of Nephrology WCN 2023, Bangkok
Related Report
Int'l Joint Research
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