Beta-catenin Signaling and Podocyte Dysfunction

描述（由申请人提供）：该申请是申请人长期努力阐明慢性肾脏疾病（CKD）发病机制的细胞和分子途径的延续，其中大多数源于肾小球病变。蛋白尿，由肾小球滤过缺陷引起，是大量慢性肾病的早期标志和主要病理特征。虽然足细胞功能障碍在蛋白尿发病中起关键作用，但其潜在的介质、信号通路和机制仍不明确。申请人实验室最近的研究将异常的b-连环蛋白信号传导与足细胞损伤和蛋白尿联系起来。本研究的中心假设是：b-连环蛋白的激活在足细胞功能障碍和蛋白尿的介导中起重要作用；因此，通过小分子抑制剂（ICG-001）抑制这一信号传导为蛋白尿肾病的治疗干预提供了一种新的途径。本应用程序的总体目标是描述2-catenin及其下游靶点MMP-7在足细胞损伤和蛋白尿发病机制中的作用，并探索靶向2-catenin信号通路进行治疗干预的可行性。在Aim 1中，我们将评估一种新型小分子靶向抑制2-catenin在三种蛋白尿肾病模型中的可行性和有效性。在Aim 2中，我们将研究2-catenin致病作用的机制，并探讨抑制2-catenin如何在体外保护足细胞完整性。最后，我们将重点关注2-catenin的一个主要靶点，MMP-7，并研究其在Aim 3中蛋白尿发病机制中的作用。这些研究可能为理解蛋白尿的病理机制提供基础和重要的见解，并为开发b-连环蛋白信号作为治疗靶点提供基础。提出的研究可能对设计未来治疗蛋白尿肾病的治疗方案具有广泛的潜在意义。

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. PUBLIC HEALTH RELEVANCE: It is estimated that up to 13% of the US adult population has some degree of chronic kidney disease (CKD), and the leaks of protein to urine (proteinuria) is an early hallmark and principal pathologic feature of a large number of CKD. The studies proposed in this application promise to provide important insights into understanding the mechanism of proteinuria, and may offer unique opportunities for designing rational strategies for the treatment of human proteinuric CKD.