2022 Fiscal Year Final Research Report
Elucidation of the mechanism of foot process regulation of renal glomerular podocytes
Project/Area Number |
20K16848
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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Research Institution | Tokyo Medical and Dental University |
Principal Investigator |
Udagawa Tomohiro 東京医科歯科大学, 東京医科歯科大学病院, 助教 (30623392)
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Project Period (FY) |
2020-04-01 – 2023-03-31
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Keywords | 蛋白尿 / WT1 / ネフローゼ症候群 |
Outline of Final Research Achievements |
In minimal change nephrotic syndrome, the foot process structure of renal podocytes (Pd) undergoes reversible morphological changes. In this study, we aimed to elucidate the mechanism of morphological regulation by genetic analysis of drug-induced Pd damage and its recovery process in mice expressing EGFP-mCherry in the Pd-specific transcription factor WT1. The project ended in failure. On the other hand, we discovered a mutation in the Zinc finger domain of WT1 in a patient with focal segmental sclerosis to stage renal failure. Renal section staining showed decreased WT1 and Pd protein expression, and forced expression of mutant WT1 in cultured cells resulted in decreased downstream gene expression. One aspect of the pathogenesis of the disease was revealed.
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Free Research Field |
小児 腎糸球体疾患
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Academic Significance and Societal Importance of the Research Achievements |
蛋白尿は末期腎不全のリスク要因である。蛋白尿が生じる病態解明を解明し、新規治療標的を明らかにすることは人類にとって有意義である。我々は蛋白尿モデルマウスと患者変異を用いてその病態発症機序の解明を目指した。巣状分節性糸球体硬化症患者で新たに見つかったZinc finger領域の変異のついて解析した所、変異WT1は細胞内局在の変化と下流蛋白遺伝子の発現低下と局在変化をもたらすと判明した。ポドサイトのWT1制御機構の一端が明らかとなり、今後末期腎臓病へと進展するこの病態の詳細な検討から、ポドサイトを修復するような機序や薬剤の開発の礎となる可能性がある。
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