A Model for Polycystic Kidney Disease in C elegans

描述（申请人摘要）：常染色体显性多囊肾 ADPKD的发病率为1/1000，通常导致终末期 肾衰竭PKD 1或PKD 2突变占所有突变的95%。 例ADPKD 1和ADPKD 2在表型上是不可区分的，导致ADPKD 1和ADPKD 2在表型上是不可区分的。 假设病理是由同一途径的缺陷引起的。的 PKD 1和PKD 2基因产物（多囊蛋白1和多囊蛋白 （2）仍然是未知的。强大的分子遗传学工具 线虫秀丽隐杆线虫（C. Elegans）将使我们能够解决 关于多囊蛋白功能和生理相关性的基本问题 合作伙伴的互动。梭PKD 1和PKD 2的线虫同源物，LOV-1和 PKD-2在三种类型的雄性化学感受器中共表达和共定位 神经元：头CEMs，HOB钩神经元和射线神经元。 此外，lov-1和pkd-2在男性神经系统中是必需的， 对雌雄同体接触的反应的交配行为和 雌雄同体外阴（Lov.）梭Tg 737（一种鼠基因 与常染色体隐性PKD相关）表现出表达模式， 与lov-1和pkd-2部分重叠，与osm-5的映射关系密切。OSM-5是 也是反应和洛夫行为所必需的，这表明这三个人可能 在同一个细胞中工作。本提案旨在检验以下假设： LOV-1、PKD-2和可能的CeTg 737在共同途径中起作用。实验将 探索LOV-1、PKD-2和CeTg 737功能的几种模型。假设 CeTg 737可以将LOV-1和PKD-2定位于纤毛， LOV-1和PKD-2是功能所必需的。此外，LOV-1可能参与了 通过纤毛中的PKD-2转导细胞外信号， 细胞内信号通路的激活。或者，LOV-1和 PKD-2可能参与感觉纤毛的形成和维持， 神经元细胞极性的建立和维持。一些 提出了补充研究以解决C. elegans 多囊藻毒素和CeTg 737对雄性交配行为的影响。遗传和分子 将探索lov-1、pkd-2和CeTg 737之间的相互作用。蜂窝 C.将确定秀丽隐杆线虫多囊藻毒素。的功能 将测定CeTg 737在雄性感觉交配行为中的作用。中的新部件 将分离LOV/PKD途径。这些实验将分析LOV/PKD， 细胞、基因和分子水平。

DESCRIPTION (Applicant's Abstract): Autosomal Dominant Polycystic Kidney Disease (ADPKD) strikes 1 in 1000 individuals, often resulting in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95 percent of all cases. ADPKD1 and ADPKD2 are phenotypically indistinguishable, leading to the hypothesis that pathology is caused by defects in the same pathway. The cellular roles of the PKD 1 and PKD2 gene products (polycystin 1 and polycystin 2, respectively) still remain unknown. The powerful molecular genetic tools of the nematode Caenorhabditis elegans (C. Elegans)will enable us to address fundamental questions regarding polycystin function and physiological relevance of partner interactions. The C. elegans homologs of PKD1 and PKD2, LOV-1 and PKD-2, are coexpressed and colocalized in three types of male chemosensory neurons: the cephalic CEMs, the HOB hook neuron, and the ray neurons. Furthermore, lov-1 and pkd-2 are required in the male nervous system for the mating behaviors of response to hermaphrodite contact and location of the hermaphrodite vulva (Lov). The C. elegans homolog of Tg737 (a murine gene associated with Autosomal Recessive PKD) exhibits an expression pattern that partially overlaps with lov-1 and pkd-2 and maps closely to osm-5. osm-5 is also necessary for response and Lov behavior, suggesting that the three may operate in the same cell. This proposal is designed to test the hypothesis that LOV-1, PKD-2, and possibly CeTg737 act in a common pathway. Experiments will explore several models of LOV-1, PKD-2, and CeTg737 function. Hypotheses include the following: CeTg737 may localize LOV-1 and PKD-2 to the cilia where LOV-1 and PKD-2 are required for function. Moreover, LOV-1 may be involved in transducing an extracellular signal via PKD-2 in the cilia, culminating in activation of an intracellular signaling pathway. Alternatively, LOV-1 and PKD-2 may be involved in the formation and maintenance of sensory cilia or the establishment and maintenance of neuronal cell polarity. A number of complementary studies are proposed to address the function of the C. elegans polycystins and CeTg737 in male mating behavior. Genetic and molecular interactions between lov-1, pkd-2, and CeTg737 will be explored. Cellular functions of the C. elegans polycystins will be ascertained. The function of CeTg737 in male sensory mating behaviors will be determined. New components in the LOV/PKD pathway will be isolated. These experiments will analyze LOV/PKD at the cellular, genetic, and molecular levels.