BIOLOGY OF EARLY RENAL CYSTOGENESIS IN THE CPK MOUSE

描述(改编自调查人员摘要)：新出现的证据 表明肾囊性疾病在人类和小鼠模型中都涉及一种 疾病易感基因通过细胞作用的多基因途径 隐性机制。这些基因似乎也在肾脏中起着关键作用。 分化和成熟。CPK小鼠是第一个多囊肾 疾病(PKD)模型被描述，因此，它已经是最 具有广泛的特征。虽然这些研究做出了重大贡献 据我们对肾囊性疾病的了解，他们已经进行了 主要用于患有晚期肾囊性疾病的小鼠。因此，关键是 正常上皮细胞分化与初始分化的关系 肾囊肿形成的事件及其分子基础尚待阐明 CPK的表型尚不清楚。 PI的最终目标是(1)表征CPK基因的作用 通过确定其在肾脏发育中的分子途径 功能，以及(2)阐明该基因的功能丧失如何导致 肾囊肿形成。在这项赠款申请中，私人投资公司建议建立 这些研究的生物学和分子框架。该提案是 分成两个互补的项目。首先，在目标1中，他们提议测试 关于肾囊性病变的流行假说是否适用于 基因定义的胎儿CPK模型，他们最近描述了这种模型。 其次，他们提议克隆CPK基因。目标2涉及到建筑 关键CPK间期的完整成绩单地图。AIM 3涉及的是 从生成的转录图中鉴定CPK基因。在AIM 4中，他们 建议检测CPK基因在时间和空间上的表达 肾脏器官发生的阶段，如干细胞的诱导、获取 性格，命运决定，凝结，上皮形成，极化， 和成熟。

DESCRIPTION (Adapted from the investigator's Abstract): Emerging evidence indicates that renal cystic disease in both humans and mouse models involves a multigenic pathway in which the disease-susceptibility genes act by cellular recessive mechanisms. These genes also appear to play critical roles in renal differentiation and maturation. The cpk mouse was the first polycystic kidney disease (PKD) model to be described and as such, it has been the most extensively characterized. While these studies have significantly contributed to our understanding of renal cystic disease, they have been conducted primarily in mice with advanced renal cystic disease. Therefore, the critical relationship between the normal epithelial differentiation and the initial events of renal cyst formation remains to be elucidated and the molecular basis for the cpk phenotype is as yet unknown. The ultimate goals of the PI are (1) to characterize the role of the cpk gene product in renal development by determining the molecular pathways in which it functions, and (2) to elucidate how the loss of function of this gene causes renal cyst formation. In this grant application, the PI proposes to establish the biologic and molecular framework for these investigations. The proposal is divided into two complementary projects. First, in Aim 1, they propose to test whether the prevailing hypotheses regarding renal cystogenesis apply to the genetically-defined, fetal cpk model that they have recently characterized. Second, they propose to clone the cpk gene. Aim 2 deals with the construction of a complete transcript map of the critical cpk interval. Aim 3 deals with the identification of the cpk gene from the transcript map generated. In Aim 4 they propose to examine the temporal and spatial expression of the cpk gene during the stages of renal organogenesis, e.g. induction, acquisition of stem cell character, fate determination, condensation, epitheliogenesis, polarization, and maturation.