Regulation of podocyte function by hic-5

描述(申请人提供)：足细胞足突(FP)和插入的裂隙横隔膜(SD)形成蛋白质丢失的最终屏障，解释为什么足细胞损伤通常与明显的蛋白尿有关。以FP消失、SD中断和蛋白尿为代表的足细胞功能障碍通常是进展性肾脏疾病的起点。在这里，我们建议验证我们的中心假设，即足细胞HIC-5表达的诱导通过增加足细胞与细胞外基质(ECM)/肾小球基底膜(GBM)的粘附性而参与蛋白尿的发病。我们进一步假设，在局灶性节段性肾小球硬化(FSGS)中足细胞HIC-5的持续表达赋予了衰老表型，从而促进了向ESRD的进展。为了检验这一假设，我们提出了三个具体目标。第一个目标将确定HIC-5增加足细胞与ECM的黏附，从而改变细胞的运动、存活和衰老的分子机制。特定目的二旨在测试诱导小鼠足细胞特异性HIC-5表达是否会导致蛋白尿。第三个目的是确定HIC-5在足细胞中的长期表达是否会导致肥大、衰老和细胞凋亡，从而导致FSGS和进展为ESRD。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生的生物学机制，并为治疗策略的发展提供新的靶点。从长远来看，这将使我们能够开发新的足细胞保护性疗法，通过抑制hic-5介导的足细胞与基底膜的黏附增加来治疗蛋白尿性肾脏疾病。这种HIC-5阻断化合物也可能通过抑制HIC-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.