FUNCTIONAL ANALYSIS OF POLYCYSTIN IN DROSOPHILA

果蝇多囊素的功能分析

基本信息

批准号：
6195475
负责人：
XIANGYI LU
金额：
$ 15.5万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-30 至 2000-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6195475
关键词：
Drosophilidae biological signal transduction chromosome deletion expression cloning gene interaction gene mutation genetic library genetic models genetic promoter element in situ hybridization laboratory mouse membrane proteins model design /development phenotype polycystic kidney

项目摘要

Description: (Taken directly from the application) Polycystic kidney disease (PKD) is a multigene disorder characterized by the growth of fluid-filled cysts, mainly in the kidney. Mutations in at least three genes, PKD1, PKD2 and PKD3, may give rise to the autosomal dominant form of PKD (ADPKD). Evidence suggests that the etiology of cyst initiation associated with PKD1 mutations results from two separate gene inactivation events. The first is an inherited mutation in one PKD1 allele; the second mutation arises in the normal allele during kidney development or maturation. We will test this "second hit" hypothesis as a mechanism for the onset of polycystic kidney disease by producing mice containing both a primary mutation in Pkd1 and a conditional second-hit mutation that can be induced somatically in the other murine Pkd1 allele. These mice will be analyzed for phenotypes associated with ADPKD. Additionally, the combination of mutations will test the Pkd1 missense mutation (Project 3) in a more physiologically relevant model. Finally, the long-range goal of this project is to generate an animal model in which the development of renal, hepatic and other pathophysiology associated with polycystic kidney disease can be analyzed and understood and in which modes of treatment can be tested.

描述：（直接摘自申请）多囊肾病（PKD）是一种多基因疾病，其特征是充满液体的囊肿生长，主要在肾脏中。至少 PKD1、PKD2 和 PKD3 三个基因的突变可能导致常染色体显性形式的 PKD (ADPKD)。有证据表明，与 PKD1 突变相关的囊肿起始病因是由两个独立的基因失活事件引起的。第一个是 PKD1 等位基因的遗传突变；第二个突变发生在肾脏发育或成熟过程中的正常等位基因中。我们将通过生产同时含有 Pkd1 初级突变和可在其他小鼠 Pkd1 等位基因中诱导体细胞诱导的条件性二次打击突变的小鼠来测试这种“二次打击”假设作为多囊肾病发病机制。将分析这些小鼠与 ADPKD 相关的表型。此外，突变组合将在生理学更相关的模型中测试 Pkd1 错义突变（项目 3）。最后，该项目的长期目标是建立一种动物模型，可以分析和理解与多囊肾病相关的肾脏、肝脏和其他病理生理学的发展，并可以测试治疗模式。