Regulation of podocyte function by hic-5

描述（由申请人提供）：足细胞足突（FPs）和中间狭缝隔膜（SD）形成蛋白质损失的最终屏障，解释了为什么足细胞损伤通常与显著的蛋白尿相关。足细胞功能障碍，以FP消退、SD破坏和蛋白尿为代表，往往是进行性肾脏疾病的起点。在这里，我们提出验证我们的中心假设，即通过增加足细胞对细胞外基质(ECM)/肾小球基底膜（GBM）的粘附性，诱导足细胞中hic-5的表达有助于蛋白尿的发病机制。我们进一步假设，足细胞hic5在局灶节段性肾小球硬化（FSGS）中的持续表达赋予了衰老表型，从而促进了ESRD的进展。为了验证这一假设，我们提出了三个具体目标。第一个目标将定义hic5增加足细胞粘附到ECM的分子机制，从而改变细胞运动、存活和衰老。特异性目的2旨在测试小鼠足细胞特异性hic-5表达的诱导是否会引起蛋白尿。第三个目的是确定hic-5在足细胞中的长时间表达是否会诱导肥大、衰老和凋亡，从而导致FSGS和ESRD的发展。如果我们的假设是正确的，这里提出的工作将具有广泛的意义，因为它将使我们更好地了解进行性蛋白尿肾病发展的生物学机制，并为制定治疗策略提供新的靶点。从长远来看，这应该使我们能够开发出新的足细胞保护疗法，通过抑制高铁-5介导的足细胞对GBM的粘附性增加来治疗蛋白尿肾病。这些高素-5阻断化合物也可能通过抑制高素-5介导的足细胞衰老来减缓FSGS向ESRD的进展。

DESCRIPTION (provided by applicant): Podocyte foot processes (FPs) and the interposed slit diaphragm (SD) form the final barrier to protein loss, explaining why podocyte injury is typically associated with marked proteinuria. Podocyte dysfunction, represented by FP effacement, disruption of the SD and proteinuria, is often the starting point for progressive kidney disease. Here we propose to test our central hypothesis that the induction of hic-5 expression in podocytes contributes to the pathogenesis of proteinuria by increasing the adhesiveness of podocyte to the extracellular matrix (ECM)/glomerular basement membrane (GBM). We further hypothesize that the persistence of podocyte hic-5 expression in focal segmental glomerulosclerosis (FSGS) confers a senescence phenotype, thereby promoting the progression to ESRD. To test this hypothesis, we propose three Specific Aims. The first Aim will define the molecular mechanism whereby hic-5 increases podocyte adhesion to the ECM, thereby altering cell motility, survival and senescence. Specific Aim two seeks to test whether the induction of podocyte-specific hic-5 expression in mice causes proteinuria. The third Aim will establish whether the prolonged expression of hic-5 in podocytes induces hypertrophy, senescence and apoptosis, thereby causing FSGS and progression to ESRD. If our hypothesis is correct, the work proposed here will have broad significance because it will provide us with a better understanding of the biological mechanism underlying the development of progressive proteinuric kidney diseases and offers a new target for the development of treatment strategies. This should in the long- term enable us to develop novel, podocyte-protective therapies that tackle proteinuric kidney diseases by suppressing the hic-5 mediated increased adhesion of podocytes to the GBM. Such hic-5 blocking compounds may also slow the progression of FSGS to ESRD by inhibiting the hic-5 mediated senescence of podocytes.