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Mechanism of Renal Cell Injury

肾细胞损伤机制

基本信息

批准号：
8696794
负责人：
GOUTAM GHOSH CHOUDHURY
金额：
--
依托单位：
SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696794
关键词：
1-Phosphatidylinositol 3-Kinase 2-tyrosine 5&apos Flanking Region Address Adenoviruses Albumins Antibodies Biological Assay Cell Proliferation Cell physiology Cells Creatinine Creatinine clearance measurement DNA DNA biosynthesis Data Disease Disease Progression Dominant-Negative Mutation Drug Design Electrophoretic Mobility Shift Assay Elements End stage renal failure Enzymes Excretory function Experimental Models Firefly Luciferases Gene Transfer Genes Genetic Transcription Glomerulonephritis Growth Factor Guanosine Triphosphate Phosphohydrolases Hour Human IkappaB kinase Immunoblot Analysis Immunoblotting Immunofluorescence Immunologic Immunohistochemistry Immunoprecipitation Isoenzymes Kidney Mediating Messenger RNA Modality Modeling Molecular Molecular Mechanisms of Action Monomeric GTP-Binding Proteins Pathogenesis Pathology Phosphorylation Phosphotransferases Plasmids Platelet-Derived Growth Factor Platelet-Derived Growth Factor Receptor Platelet-Derived Growth Factor beta Receptor Play Population Process Proliferating Cell Nuclear Antigen Proliferative Glomerulonephritis Protein Tyrosine Kinase Proteins Ras homolog enriched in brain Rattus Regulation Renal function Reporter Role SRC gene SU 6656 Sequence Analysis Signal Pathway Signal Transduction Signal Transduction Pathway Staining method Stains Structure of glomerular mesangium Techniques Testing Therapeutic Therapeutic Effect Transcription Initiation Site Transfection Veterans anti-Thy-1 cell injury cell motility chromatin immunoprecipitation cytokine design in vivo inhibitor/antagonist kidney cell mesangial cell migration mutant p65 promoter protein expression protein-tyrosine kinase c-src receptor upregulation research study response small hairpin RNA urinary

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）：