BIOLOGY OF EARLY RENAL CYSTOGENESIS IN THE CPK MOUSE

CPK 小鼠早期肾细胞发生的生物学

• 批准号: 6042653
• 负责人: Lisa M Guay-Woodford
• 金额: $ 20.16万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6042653
• 关键词: disease /disorder model; gene expression; genetic mapping; genetic susceptibility; histogenesis; in situ hybridization; kidney; laboratory mouse; molecular cloning; molecular pathology; pathologic process; polycystic kidney

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.

描述（改编自研究者的摘要）：新出现的证据 表明人类和小鼠模型中的肾囊性疾病涉及 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病中发挥着关键作用。 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，它是最 广泛表征。虽然这些研究做出了重大贡献 根据我们对肾囊性疾病的了解，他们已经进行了 主要针对患有晚期肾囊性疾病的小鼠。因此，关键的 正常上皮分化与初始分化之间的关系 肾囊肿形成的事件仍有待阐明，其分子基础 cpk 表型尚不清楚。 PI的最终目标是（1）表征cpk基因的作用 通过确定产品在肾脏发育中的分子途径 功能，以及（2）阐明该基因功能丧失如何导致 肾囊肿形成。在本次拨款申请中，PI 建议建立 这些研究的生物学和分子框架。该提案是 分为两个互补的项目。首先，在目标 1 中，他们建议测试 关于肾囊肿发生的流行假设是否适用于 他们最近描述了基因定义的胎儿 cpk 模型。 其次，他们建议克隆cpk基因。目标 2 涉及建设 关键 cpk 间隔的完整转录图谱。目标 3 涉及 从生成的转录图谱中鉴定 cpk 基因。在目标 4 中，他们 建议检查 cpk 基因的时间和空间表达 肾器官发生的阶段，例如诱导、获得干细胞 性格、命运决定、凝结、上皮生成、极化、 和成熟。