TRPC-mediated calcium signaling in podocytes

足细胞中 TRPC 介导的钙信号传导

基本信息

批准号：
8542130
负责人：
Anna Greka
金额：
$ 15万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-25 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8542130
关键词：
Actin-Binding Protein Actins Agreement Angiotensin II Area Calcineurin Calcineurin inhibitor Calcium Signaling Calmodulin Cells Chronic Kidney Failure Cyclic AMP-Dependent Protein Kinases Cyclosporine Cytoskeleton Data Development Diabetic Nephropathy Disease Epidemic Equilibrium Extravasation Family Feedback Feeds Fiber Filtration Focal Segmental Glomerulosclerosis Glomerular Capillary Goals Guanosine Triphosphate Phosphohydrolases Health Healthcare Heart Hypertrophy Homeostasis In Vitro Injury Kidney Kidney Diseases Kidney Failure Laboratories Link Lipopolysaccharides Maintenance Mediating Membrane Modeling Molecular Morbidity - disease rate Mus Mutation Nephrotic Syndrome Pathogenesis Pathway interactions Pericytes Phase Phenocopy Phenotype Phosphoric Monoester Hydrolases Phosphotransferases Process Prognostic Marker Proteins Proteinuria Publishing Renal Hypertension Research Research Personnel Role Signal Transduction Stimulus Stress Fibers Structure Testing Urine Work base cardiovascular risk factor cell motility human disease in vivo insight interest migration mortality new therapeutic target novel podocyte receptor response to injury rho role model synaptopodin

项目摘要

PROJECT SUMMARY Proteinuria is a major health-care problem, not only as a cardinal sign and prognostic marker of kidney disease, but also importantly, as an independent risk factor for cardiovascular morbidity and mortality. Kidney podocytes are important for the maintenance of the kidney filtration barrier. Early podocyte injury is characterized by dysregulation of Ca2+ signaling, leading to proteinuria, the inappropriate leakage of protein into the urine. Work by the PI and others has shown that Ca2+ signals, mediated by TRP (Transient Receptor Potential) channels, are enriched near the leading edge of migrating cells. Ongoing work in the PI's laboratory has shown that Ca2+ influx through TRPC5 and TRPC6 channels in podocytes is criticaly important for the cytoskeletal integrity of these cells. TRPC5-mediated Ca2+ influx induces Rac1 activation, thereby promoting podocyte migration. In contrast, TRPC6-mediated Ca2+ influx increases RhoA activity, inhibiting podocyte migration. Here we propose to test our central hypothesis that disruption of the critical balance between TRPC5 and TRPC6 signaling contributes to the pathogenesis of proteinuria. We are specificaly interested in the role of TRPC5 and Rac1 signaling in early phases of proteinuric kidney disease. To test this hypothesis, our first aim is to explore whether TRPC channels regulate actin dynamics by modulating synaptopodin and RhoGTPase activity in podocytes. In our second aim, we wil explore the in vivo role of podocyte TRPC5 signaling in the pathogenesis of proteinuria, and thus its potential as a new therapeutic target for diseases such as nephrotic syndrome, FSGS, diabetic and hypertensive nephropathy. This area of research is currently highly relevant to human disease, since TRPC-mediated podocyte damage leads to proteinuria, and in turn, proteinuria is a herald of chronic kidney disease and kidney failure, both of which are on the rise, and have been recently described by many observers as an impending epidemic. ! !

项目摘要蛋白尿是一个主要的医疗保健问题，不仅是肾脏的主要标志和预后标记疾病，但同样重要的是，作为心血管发病率和死亡率的独立危险因素。肾足细胞对于维持肾脏过滤屏障很重要。早期的足细胞损伤是以Ca2+信号传导失调的特征，导致蛋白尿，蛋白质的不当泄漏进入尿液。 PI和其他人的工作表明，由TRP（瞬态受体电势）介导的Ca2+信号通道在迁移细胞的前缘附近富集。 PI实验室正在进行的工作已显示在足细胞中通过TRPC5和TRPC6通道的Ca2+涌入对于细胞骨架至关重要这些细胞的完整性。 TRPC5介导的Ca2+流入诱导Rac1激活，从而促进足细胞迁移。相反，TRPC6介导的Ca2+流入增加了RhoA活性，抑制了足细胞的迁移。在这里，我们建议测试我们的中心假设，即TRPC5和 TRPC6信号传导有助于蛋白尿的发病机理。我们对角色感兴趣蛋白尿肾脏疾病早期阶段的TRPC5和RAC1信号传导。为了检验这一假设，我们的第一个目标是探索TRPC通道是否通过调节突触蛋白和Rhogtpase来调节肌动蛋白动力学足细胞的活性。在我们的第二个目标中，我们将探索Podocyte TRPC5信号传导的体内作用蛋白尿的发病机理，因此作为肾病等疾病的新治疗靶标的潜力综合征，FSG，糖尿病和高血压肾病。由于TRPC介导的足细胞损伤，该研究领域目前与人类疾病高度相关导致蛋白尿，进而导致蛋白尿是慢性肾脏疾病和肾衰竭的先驱，两者都这正在上升，最近许多观察家将其描述为即将来临的流行病。呢呢