Glomerular Capillaries-- Normal and Pathologic

肾小球毛细血管——正常和病理

• 批准号: 8792268
• 负责人: MARILYN Gist FARQUHAR
• 金额: $ 52.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792268
• 关键词: Adriamycin PFS; Affect; Animals; Apoptosis; Binding; Biochemical; Biological Assay; Cell Survival; Cells; Complex; Data; Development; Diabetic Nephropathy; Disease; Fluorescence; Focal Adhesions; Focal glomerulosclerosis; Glomerular Capillary; Glomerulonephritis; Goals; Grant; Image; In Situ; Injury; Instruction; Intercellular Junctions; Kidney; Knock-out; Knockout Mice; Life; Ligation; Mediating; Molecular; Mus; Nephrosis; Pathologic; Permeability; Phenotype; Play; Principal Investigator; Process; Progress Reports; Proteins; Proteinuria; Proteomics; Renal glomerular disease; Research; Role; Signal Pathway; Signal Transduction; Testing; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vinculin; Work; absorption; cellular imaging; db/db mouse; glomerular filtration; insight; mutant; nephrin; novel; podocyte; research study; response; slit diaphragm

During the last 39 years under this grant our research has been directed toward understanding the cellular and molecular mechanisms of glornerular permeability and protein absorption as well as the derangements in these processes that occur in glomerular diseases. The experiments proposed in this application represent a direct continuation of our ongoing work on characterization of slit diaphragms and the role of GIV in podocyte function and survival after podocyte injury. We will focus on three specific aims: Specific Aim # 1 : To characterize and determine the functions of novel, putative slit diaphragm components identified by MS and quantitative organellar proteomics in slit diaphragm fractions. We will verify their junctional localization and determine their binding partners and functions in podocytes. Specific Aim #2: To investigate the role of GIV in mediating Akt signaling and cell survival in passive Heymann nephritis, focal glomerulosclerosis, and diabetic nephropathy. In PAN nephrosis GIV is upregulated, assembles a VEGFR2/GIV/Gal3 complex, and functions to maintain podocyte survival. We will determine if GIV plays a similar role in other diseases associated with podocyte injury. Specific Aim #3: To further investigate the mechanisms and spatial-temporal aspects of GIV's effects on podocytes. Our preliminary data indicate that GIV might function at focal adhesions (FA) and/or at slit diaphragms as it colocalizes with vinculin and VEGFR2 at FA and it binds CD2AP. We will investigate the dynamics ofthe interactions between GIV and VEGFR2 and CD2AP by live cell imaging, use proximity ligation assays and superresolution IF imaging (STORM) to determine where interaction occurs, and test whether GIV depletion or expression of GIV mutants affect FA or junction formation. These studies can be expected to provide novel insights into understanding ofthe cellular and molecular mechanisms of glomerular filtration and glomerular injury and their alterations in glomerular diseases associated with proteinuria. RELEVANCE (See instructions): Podocyte injury is the initiating cause of many glomerular diseases. The studies planned will provide key insights into the signaling neworks that regulate podocyte organization, functions and survival in response to glomerular injury in diseases associated with proteinuria.

在过去的39年里，在这项资助下，我们的研究一直致力于了解