Beta-catenin Signaling and Podocyte Dysfunction

β-连环蛋白信号传导和足细胞功能障碍

• 批准号: 8236328
• 负责人: YOUHUA LIU
• 金额: $ 22.57万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-10 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236328
• 关键词: Ablation; Adriamycin PFS; Adult; Albuminuria; Charge; Chronic Kidney Failure; Data; Development; Diabetic Nephropathy; Ectopic Expression; End stage renal failure; Endothelium; Filtration; Focal Segmental Glomerulosclerosis; Foot Process; Foundations; Functional disorder; Future; Gene Targeting; Genes; Genetic; Goals; Human; In Vitro; Inherited; Injury; Kidney; Kidney Diseases; Laboratories; Lesion; Link; Matrilysin; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nephrons; Pathogenesis; Pathologic; Pathway interactions; Patients; Play; Population; Proteins; Proteinuria; Renal glomerular disease; Role; Shapes; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Treatment Protocols; Urine; base; beta catenin; clinically relevant; design; glomerular basement membrane; glomerular filtration; glomerulosclerosis; in vivo; inhibitor/antagonist; insight; integrin-linked kinase; migration; molecular sieving; nephrogenesis; novel; novel strategies; peptidomimetics; podocyte; prevent; protective effect; slit diaphragm; small molecule; therapeutic target; treatment strategy

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.

描述（由申请人提供）：本申请是申请人长期致力于阐明慢性肾脏疾病（CKD）发病机制中的细胞和分子途径的延续，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。虽然足细胞功能障碍在蛋白尿的发病中起着关键作用，但其潜在的介质、信号通路和机制仍不清楚。来自申请人实验室的最近研究已经将异常b-连环蛋白信号传导与足细胞损伤和蛋白尿联系起来。本申请的中心假设是：β-连环蛋白激活在介导足细胞功能障碍和蛋白尿中起着至关重要的作用;因此，通过小分子抑制剂（ICG-001）抑制这种信号传导提供了一种用于蛋白尿肾病的治疗干预的新方法。本申请的总体目标是描述2-连环蛋白及其下游靶标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-连环蛋白信号传导用于治疗干预的可行性。在目标1中，我们将评估在三种蛋白尿肾病模型中通过新型小分子靶向抑制2-连环蛋白的可行性和有效性。在目标2中，我们将研究2-catenin致病作用的机制，并探索如何抑制2-catenin导致体外足细胞完整性的保护。最后，我们将集中在一个主要的目标2-连环蛋白，MMP-7，并探讨其作用的发病机制中的蛋白尿的目的3。这些研究将为蛋白尿发病机制的研究提供基础和重要的信息，并为开发β-连环蛋白信号通路作为治疗靶点提供基础。拟议的研究可能对设计未来蛋白尿性肾病的治疗方案具有广泛的意义。 公共卫生关系：据估计，高达13%的美国成年人患有一定程度的慢性肾病（CKD），蛋白质渗漏到尿液中（蛋白尿）是大量CKD的早期标志和主要病理特征。本申请中提出的研究有望为理解蛋白尿的机制提供重要的见解，并可能为设计治疗人类蛋白尿CKD的合理策略提供独特的机会。