| Project/Area Number |
14571018
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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 |
Kidney internal medicine
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| Research Institution | NIIGATA UNIVERSITY |
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Principal Investigator |
SAITO Akihiko NIIGATA UNIVERSITY, Graduate School of Medical and Dental Sciences, Visiting Associate professor, 大学院・医歯学総合研究科, 客員助教授 (80293207)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEDA Tetsuro NIIGATA UNIVERSITY, Graduate School of Medical and Dental Sciences, Visiting Assistant, 大学院・医歯学総合研究科, 客員助手 (10361924)
TABATA Yasuhiko Kyoto University, Institute of Frontier Medical Sciences, Professor, 再生医科学研究所, 教授 (50211371)
GEJYO Fumitake NIIGATA UNIVERSITY, Medical and Dental Hospital, Professor, 医歯学総合病院, 教授 (20126410)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | megalin / regenerative medicine / AGE / diabetic nephropathy / dialysis-related amyloidosis / uremic toxin protein / leptin / Dent's disease / 肝型脂肪酸結合蛋白 / エンドサイトーシス |
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| Research Abstract |
Megalin is an endocytosis receptor that is expressed abundantly in the apical membranes of proximal tubule cells. It functions for absorption and degradation of low-molecular-weight proteins filtered by glomeruli. We analyzed the functions of megalin and carried out basic studies for its application to clinical nephrology and regenerative medicine. The main research results are as follows :
1)We investigated the role of megalin in the endocytosis of glucose-modified advanced glycation end products(AGE) that participate in the pathogenesis of diabetic nephropathy. We and the presence of a novel AGE-binding protein (ref.1). We completed the identification of the protein and are in the process of studying its pathophysiological relevance. We also found that megalin binds carbonyl compound-modified AGE and is involved in the cellular uptake.
2)We reported a therapeutic model for bioengineered implantation of megalin-expressing cells in renal failure to remove β_2-microglobulin, a uremic toxin protein inducing dialysis-related amyloidosis (ref.2). We identified that megalin is expressed in the human amniotic cells that have been used for clinical implantation therapies for lysozomal enzyme deficiency.
3)We found that the renal metabolism of leptin, a putative uremic toxin protein, is mediated by megalin but not by the leptin receptors. We analyzed the binding affinity of megalin with leptin using quartz-crystal microbalance.
4)We identified a novel CLCN5 gene mutation in Dent' disease with hereditary low-molecular-weight proteinuria, and revealed decreased renal expression of megalin in the kidney biopsy specimens.
5)To induce hepatic gene expression of megalin in renal failure, we developed a strategy to express megalin in the basolateral cellular membrances (ref.3).
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