Yale Center for the Study of Polycystic Kidney Disease

总体中心描述（由申请人提供）： 耶鲁多囊肾病跨学科研究中心的总体目标是阐明多囊蛋白基因缺陷导致常染色体显性多囊肾病（ADPKD）的机制，并了解改变疾病表型表达的因素。在该中心资助的前5年进行的研究为我们目前理解PC-1/PC-2相互作用在抑制囊肿形成中的重要性提供了基础，建立了纤毛在多种形式的囊性疾病中的核心作用，并促进了关于多囊蛋白如何在细胞中加工和运输的新概念。在该奖项的更新中，这些结果已被用于将研究重点放在受调控的翻译后修饰和多囊蛋白的运输领域，以及它们在纤毛功能和信号传导中的作用。为了研究这一假设，Somlo的项目将定义PC-1和PC-2如何运输到纤毛，并将确定这些蛋白质中介导运输的结构域，并确定该过程的分级中断是否可以直接促进动物模型中的囊肿形成。Caplan的项目将探索PC-1切割的C-末端结构域的信号作用，以及PC-2如何调节信号作用。Sun的项目利用斑马鱼遗传筛选的力量来鉴定一种独特的纤毛蛋白，该蛋白在斑马鱼模型中模拟PKD的许多方面，并将探索这种蛋白在正常纤毛功能中的作用。Cantley的项目将研究多囊蛋白信号传导在调节介导小管形成的形态发生事件中的作用，并将探索Ngal修饰这些信号的能力，从而抑制体内囊肿形成。埃利希的项目将利用钙通道信号传导的专业知识来定义PC-2钙通道活性如何在纤毛中调节。这些努力将得到小鼠和细胞系核心的支持，该核心具有多囊蛋白功能和ADPKD的体内动物和细胞模型的特殊阵列。 我们相信，这些项目，通过解决从不同方向的中心假设，由每个研究者的专业知识，将导致在了解ADPKD囊肿形成的发病机制方面取得实质性进展，并将为建立抑制囊肿进展的临床试验奠定基础。

DESCRIPTION OF OVERALL CENTER (provided by applicant): The overall goal of the Yale Interdisciplinary Center for Polycystic Kidney Disease Research is to elucidate the mechanisms by which defects in the polycystin genes result in autosomal dominant polycystic kidney disease (ADPKD) and to understand the factors that modify the expression of the disease phenotype. Studies performed during the first 5 years of this Center Grant have provided the foundation for our present understanding of the importance of PC-1/PC-2 interactions in suppressing cyst formation, established a central role of the cilia in multiple forms of cystic disease, and have promoted novel concepts about how polycystins are processed and traffic in the cell. In the renewal of this award, these results have been utilized to focus the research on the areas of regulated post-translational modification and trafficking of polycystins, as well as their role in ciliary function and signaling. To investigate this hypothesis, Project by Somlo will define how PC-1 and PC-2 traffic to cilia, and will identify the domains within these proteins that mediate trafficking and determine whether graded interruption of this process can directly promote cystogenesis in animal models. Project by Caplan will explore the role of signaling by the cleaved C-terminal domain of PC-1, and how this is regulated by PC-2. Project by Sun has utilized the power of zebrafish genetic screening to identify a unique ciliary protein that mimics many of the aspects of PKD in the zebrafish model and will explore the role of this protein in normal ciliary function. Project by Cantley will investigate the role of polycystin signaling in regulating the morphogenic events that mediate tubule formation, and will explore the ability of Ngal to modify these signals and thereby suppress cyst formation in vivo. Project by Ehrlich will utilize expertise in calcium channel signaling to define how PC-2 calcium channel activity is regulated in the cilia. These efforts will be supported by the Mouse and Cell Line Core that has an exceptional array of in vivo animal and cell-based models of polycystin function and ADPKD. We believe that these projects, by addressing the central hypothesis from different directions focused by the expertise of each investigator, will lead to substantial progress in understanding the pathogenesis of cyst formation in ADPKD, and will lay the groundwork for the establishment of clinical trials for suppressing cyst progression in patients with this disease.