A Model for Polycystic Kidney Disease in C elegans

描述(申请人摘要)：常染色体显性遗传性多囊肾 疾病(ADPKD)每1000人中有1人发病，通常导致终末期 肾功能衰竭。PKD1或PKD2的突变占所有突变的95% 案子。ADPKD1和ADPKD2在表型上难以区分，导致 假设病理是由同一途径中的缺陷引起的。这个 PKD-1和PKD2基因产物(多囊蛋白1和多囊蛋白)的细胞作用 2)仍不为人知。强大的分子遗传学工具 线虫秀丽线虫将使我们能够解决 关于多囊蛋白功能和生理相关性的基本问题 合作伙伴互动。线虫PKD1和PKD2、LOV-1和 PKD-2在三种类型的男性化学感觉中共表达和共定位 神经元：头CEMS、霍霍钩神经元和射线神经元。 此外，LOV-1和PKD-2在男性神经系统中也是必需的 雌雄异体接触反应的交配行为和雌蜂的位置 两性外阴(Lov)。小鼠基因Tg737的线虫同源物 与常染色体隐性遗传性PKD相关)表现出一种 与LOV-1和PKD-2部分重叠，与OSM-5紧密映射。OSM-5是 对于回应和恋爱行为也是必要的，这表明这三个人可能 在同一个单元格中运行。这项提议旨在检验这样一个假设： LOV-1、PKD-2和可能的CeTg737在一个共同的途径中起作用。实验将会 探索LOV-1、PKD-2和CeTg737功能的几种模型。假设 包括：CeTg737可将LOV-1和PKD-2定位于纤毛，其中 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，最终在 激活细胞内信号通路。或者，LOV-1和 PKD-2可能参与了感觉纤毛的形成和维持 神经细胞极性的建立和维持。一批 提出了补充研究来解决线虫的功能 多囊蛋白和CeTg737在雄性交配行为中的作用遗传和分子 我们将探索LOV-1、PKD-2和CeTg737之间的相互作用。蜂窝 线虫多囊蛋白的功能将被确定。的功能 将测定CeTg737在雄性感官交配行为中的作用。中的新组件 LOV/PKD途径将被分离。这些实验将在以下位置分析LOV/PKD 在细胞、遗传和分子水平上。

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.