| Project/Area Number |
15K08348
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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 |
Human pathology
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| Research Institution | Oita University |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | 腎癌 / 悪性化 / ノックアウトマウス / SAV1 |
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| Outline of Final Research Achievements |
SAV1 is a core component of the Hippo pathway. To analyze its implication in malignant transformation of clear cell renal cell carcinoma (ccRCC), I generated kidney-specific SAV1- or SAV1 and VHL-knockout mice. I observed many renal cysts in kidneys of SAV1 knockout mice. Renal tubular epithelial cells showed high cellularity and multiple layering, including enlargement of their nuclei. Furthermore, VHL deletion combined with SAV1 deletion was likely to inhibit cellular abnormalities shown in SAV1 knockout mice, although double knockout mice were rarely generated. These results suggest that SAV1 plays important roles for regulation of nuclear size of renal epithelial cells, and the maintenance of renal structure under physiological conditions.
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| Academic Significance and Societal Importance of the Research Achievements |
腎癌の動物モデルとして、本研究では腎尿細管に特異的なSAV1欠失により、細胞異型や細胞増殖、腎発生の異常が認められた。つまり、腫瘍抑制に働くHippoパスウェイが、VHL-HIF1パスウェイ以外でも腎の発生や癌化に関わることを初めて明らかにした。また、Hippoパスウェイがin vivoでどのように他のパスウェイと関係するかをパスウェイ解析やVHLとのダブルノックアウトマウスによって明らかにした。したがって、新たな腎発生や癌化のメカニズムの発見だけでなく、既存の分子標的治療薬がターゲットとしているVHL-HIF1パスウェイでは根治し得ない高悪性度腎癌の治療開発の礎となった。
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