Mechanism of Renal Cell Injury

肾细胞损伤机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): A major manifestation of mesangioproliferative glomerulonephritis in human and experimental model is increased expression of platelet-derived growth factor receptor-2 (PDGFR) in mesangial cells with concomitant proliferation and migration. The mechanism by which increased PDGFR results in the activation of mesangial cells is poorly understood. Our results provide first evidence that in mesangial cells PDGFR-activated phosphatidylinositol (PI) 3 kinase/Akt kinase regulates proliferation and migration. Furthermore, we demonstrate an increase in PDGFR tyrosine kinase activity, resulting in PI 3 kinase and Akt kinase activities in anti-Thy-1-induced mesangioproliferative glomerulonephritis in the rat. Moreover, the non-receptor tyrosine kinase c-Src regulates Ras-GTPase and associates with PI 3 kinase, which regulates Akt kinase activity. In this proposal, using mesangial cells in culture and glomeruli from rats with anti-Thy-1-induced glomerulonephritis, we will test the hypothesis that signal relay from c-Src to PI 3 kinase/Akt through Ras regulates the state of mesangial cell activation. In the preliminary data, we show that PDGF-stimulated Akt kinase activates I:B kinases 1 and 2, resulting in NF:B activation. Importantly, we provide the first evidence that PDGF increases expression of Akt kinase effector Rheb (Ras homolog enriched in brain). We hypothesize that Akt-dependent NF:B-mediated expression of Rheb regulates mesangial cell activation. In the first specific aim, we plan to investigate the molecular mechanisms of action of c-Src and Ras on PDGFR-stimulated PI 3 kinase/Akt signaling in mesangial cells and in glomeruli of rats with mesangioproliferative glomerulonephritis. Also a cross-talk between c-Src and Ras will be studied in mesangial cell activation. In the second specific aim, the roles of I:B kinases 1 and 2 and NF:B in mesangial cell proliferation and migration will be studied. Phosphorylation of I:B kinase isotypes and phosphorylation of their substrates in anti-Thy-1-induced glomerulonephritis will be investigated. In the specific aim 3, role of PI 3 kinase/Akt signaling and its upstream regulators Ras and c-Src in expression of Rheb will be examined. Contribution of NF:B to the Rheb expression will be investigated. To address these specific aims, techniques including immunohistochemistry/immunofluorescence, immunoprecipitation, immunoblotting, reporter transfection assays, electrophoretic mobility shift assays, chromatin immunoprecipitation asays, adenovirus-mediated gene transfer of mutant enzymes, si/shRNA expression and conditional expression of proteins will be used.
描述(由申请人提供):

项目成果

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GOUTAM GHOSH CHOUDHURY其他文献

GOUTAM GHOSH CHOUDHURY的其他文献

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{{ truncateString('GOUTAM GHOSH CHOUDHURY', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10512762
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10364352
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
BLR&D Research Career Scientist Award Application
BLR
  • 批准号:
    10047690
  • 财政年份:
    2016
  • 资助金额:
    --
  • 项目类别:
Mechanism of Renal Cell Injury
肾细胞损伤机制
  • 批准号:
    9269454
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Mechanism of Renal Cell Injury
肾细胞损伤机制
  • 批准号:
    8398924
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Renal Cell Injury
肾细胞损伤的机制
  • 批准号:
    10013592
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Renal Cell Injury
肾细胞损伤的机制
  • 批准号:
    10554236
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Mechanism of Renal Cell Injury
肾细胞损伤机制
  • 批准号:
    8043246
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Mechanisms of Renal Cell Injury
肾细胞损伤的机制
  • 批准号:
    10293566
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Mechanism of Renal Cell Injury
肾细胞损伤机制
  • 批准号:
    8253501
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

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    6758525
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    1996
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