Yale Center for the Study of Polycystic Kidney Disease

耶鲁大学多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的机制 疾病（ADPKD），并了解修饰疾病表型表达的因素。 在本中心赠款的前5年进行的研究为我们现在的研究奠定了基础。 了解PC-1/PC-2相互作用在抑制囊肿形成中的重要性，建立了一个 纤毛在多种形式的囊性疾病中的中心作用，并促进了关于如何 多囊蛋白在细胞中被加工和运输。在这个奖项的更新，这些结果已经 用于集中研究受管制的翻译后修饰和贩运的领域， 多囊蛋白，以及它们在纤毛功能和信号传导中的作用。为了研究这个假设，项目1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纤毛的结构域。 并确定这一过程的分级中断是否能直接促进膀胱生成， 动物模型项目2将探索PC-1的C端切割结构域的信号传导作用， 这是如何被PC-2控制的项目3利用斑马鱼基因筛选的力量来识别一种 一种独特的纤毛蛋白，它模拟了斑马鱼模型中PKD的许多方面，并将探索PKD的作用。 这种蛋白质在正常纤毛功能中的作用。项目4将研究多囊蛋白信号转导在调节细胞凋亡中的作用。 介导小管形成的形态发生事件，并将探讨Ngal修改这些的能力 信号，从而抑制体内囊肿形成。项目5将利用钙通道方面的专业知识 信号传导以确定PC-2钙通道活性在纤毛中是如何调节的。这些努力将 由小鼠和细胞系核心支持，该核心具有特殊的体内动物和基于细胞的 多囊蛋白功能模型和ADPKD。

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 1 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 2 will explore the role of signaling by the cleaved C-terminal domain of PC-1, and how this is regulated by PC-2. Project 3 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 4 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 5 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.