| Project/Area Number |
18590304
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Yokohama City University |
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Principal Investigator |
HIROSE Tomonori Yokohama City University, Graduate School of Medicine, Assistant Professor (20381668)
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| Co-Investigator(Kenkyū-buntansha) |
KURIHARA Hidetake Juntendo University, School of Medicine, Associate Professor (80311976)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥2,530,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | glomerular disease / kidney disease / animal models of disease / cell polarity / signal transduction / 分子病態学 |
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| Research Abstract |
We originally established a mouse model of glomerular disease by podocyte-specific deletion of aPKClambda. Clinical and histopathological examinations of blood, urine, and kidneys of these mice confirmed that they develop dysfunctions of the slit diaphragm with proteinuria, glomerulosclerosis, and renal failure. These results indicate that our mice can serve as a useful model to analyze glomerular diseases. We extended these results to reveal molecular mechanisms of glomerular diseases and obtained the following results.
1. The electron microscopic analyses of our model mice in various stages revealed a step-wise progression of defects in the slit diaphragms. Although the slit diaphragms were formed at first, they were dislocated, disorganized, and lost along with the growth of mice. The glomerular basement membranes were not significantly affected.
2. To clarify the function of aPKC in the regulation of glomerular functions, we examined the functional interactions between aPKC and the structural proteins in slit diaphragms: nephrin and podocin. We fund that a specific inhibitor for aPKC significantly disturbed the distribution of nephrin and podocin in the isolated rat glomeruli. However, the formation of nephrin-podocin complex was not significantly affected by aPKC inhibitor.
These data indicate that aPKC is required for the proper distribution of the structural proteins in slit diaphragms. It is also suggested that the functional disturbance in aPKC can be involved in the development of glomerular diseases.
Along with above observations, we revealed that aPKC regulates the restriction of a specific lipid to determine the basolateral domains and that aPKC-binding protein PAR3 plays a critical role in the establishment of apical domains.
We published and reported these results as indicated in the section 11.
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