Beta-catenin Signaling and Podocyte Dysfunction

描述(申请人提供)：这项申请是申请人长期努力的延续，目的是阐明慢性肾脏疾病(CKD)发病机制中的细胞和分子途径，其中大部分起源于肾小球病变。由肾小球滤过缺陷引起的蛋白尿是大量CKD的早期标志和主要病理特征。尽管足细胞功能障碍在蛋白尿的发病中起着关键作用，但其潜在的介导物、信号通路和机制仍不清楚。申请人实验室最近的研究表明，异常的b-连环蛋白信号与足细胞损伤和蛋白尿有关。这一应用的中心假设是：B-连环蛋白激活在介导足细胞功能障碍和蛋白尿中起重要作用；因此，小分子抑制剂(ICG-001)抑制这一信号转导为蛋白尿性肾脏疾病的治疗干预提供了一种新的途径。本应用的总体目标是阐明2-连环蛋白及其下游靶点基质金属蛋白酶-7在足细胞损伤和蛋白尿发病机制中的作用，并探讨以2-连环蛋白信号为靶点进行治疗干预的可行性。在目标1中，我们将评估一种新的小分子靶向抑制2-连环蛋白在三种蛋白尿性肾病模型中的可行性和有效性。在目标2中，我们将研究2-连环蛋白致病作用的机制，并探讨抑制2-连环蛋白如何在体外保护足细胞的完整性。最后，我们将集中于2-连环蛋白的一个主要靶点--基质金属蛋白酶-7，并在目标3中探讨其在蛋白尿发病机制中的作用。这些研究将可能为了解蛋白尿的发病机制提供基础和重要的见解，并为开发b-连环蛋白信号转导作为治疗靶点奠定基础。拟议的研究可能对设计未来治疗蛋白尿性肾脏疾病的治疗方案具有广泛的意义。

DESCRIPTION (provided by applicant): This application is a continuation of the applicant's long-term efforts to elucidate the cellular and molecular pathways in the pathogenesis of chronic kidney diseases (CKD), most of which originates from glomerular lesions. Proteinuria, resulting from defective glomerular filtration, is an early hallmark and principal pathologic feature of a large number of CKD. Although podocyte dysfunction is known to play a critical role in the onset of proteinuria, the underlying mediators, signaling pathways and mechanisms remain poorly defined. Recent studies from the applicant's laboratory have linked the aberrant b-catenin signaling to podocyte injury and proteinuria. The central hypotheses of this application are that: b-catenin activation plays an imperative role in mediating podocyte dysfunction and proteinuria; and therefore inhibition of this signaling by small molecule inhibitor (ICG-001) provides a novel approach for therapeutic intervention of proteinuric kidney diseases. The overall goal of this application is to delineate the role of 2- catenin and its downstream target MMP-7 in the pathogenesis of podocyte injury and proteinuria and to explore the feasibility of targeting 2-catenin signaling for therapeutic intervention. In Aim 1, we will evaluate the feasibility and efficacy of targeted inhibition of 2-catenin by a novel small molecule in three models of proteinuric kidney diseases. In Aim 2, we will investigate the mechanism underlying the pathogenic actions of 2-catenin and explore how inhibition of 2-catenin leading to protection of podocyte integrity in vitro. Finally, we will focus on one major target of 2-catenin, MMP-7, and investigate its role in the pathogenesis of proteinuria in Aim 3. These studies will likely offer fundamental and important insights into understanding of the patho-mechanism of proteinuria, and could provide a foundation for the exploitation of b-catenin signaling as therapeutic target. The proposed studies may potentially have wide implications in designing future therapeutic regimens for the treatments of proteinuric kidney diseases.