Characterization of the Murine pcy Mutation

鼠 pcy 突变的表征

• 批准号: 6684111
• 负责人: DAVID D WOO
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684111
• 关键词: artificial chromosomes; biotechnology; disease /disorder model; gene expression; gene mutation; genetic mapping; genetic susceptibility; laboratory mouse; molecular pathology; phenotype; polycystic kidney

Polycystic kidney diseases (PKD) are among the leading causes of progressive renal failure in children and adults. Currently, there is no known therapy that can inhibit or retard the progression to renal failure in PKD patients. Despite the recent molecular identification of PKD1 and PKD2, the two genes most commonly mutated in human PKD, the genetics and pathogenesis of renal failure in PKD remains poorly understood. Homozygous pcy/pcy mice develop a slowly progressive form PKD that has many characteristics resembling human PKD. Understanding the molecular lesion in pcy mice will provide important additional insights into the genetics and pathogenic pathways involved in the development of renal failure in PKD. This proposal aim to elucidate the molecular defect in the pcy mouse and to improve our understanding of modifier genes that determine the severity of the renal cystic disease phenotype. Towards the identification and characterization of the pcy mutation at the molecular level, we will (1) isolate the minimal pcy interval in BACs contigs using the RPCI-23 mouse genomic library for sequencing by the NIH mouse genome sequencing project and (2) identify the pcy gene by systematically characterize; candidate genes located within our pcy interval. Towards improving our understanding of modifier genes that regulates the severity of the polycystic kidney disease phenotype, we will (1) isolate the two mapped modifier loci into separate congenic strains using marker assisted selective breeding approaches and (2) use gene expression profiling to catalog the set of genes that are differentially expressed in the kidneys of congenic mice with the mild PKD and in the kidneys of age matched congenic mice with the severe PKD.

多囊肾病（PKD）是儿童和成人进行性肾衰竭的主要原因之一。目前，没有已知的疗法可以抑制或延缓PKD患者向肾衰竭的进展。 尽管最近的分子鉴定PKD 1和PKD 2，这两个基因最常见的突变在人类PKD，遗传学和肾功能衰竭在PKD的发病机制仍然知之甚少。 纯合子pcy/pcy小鼠发展为缓慢进展型PKD，其具有许多类似于人PKD的特征。 了解pcy小鼠的分子病变将为PKD肾衰竭的发生提供重要的遗传学和致病途径。 该建议旨在阐明pcy小鼠的分子缺陷，并提高我们对决定肾囊肿表型严重程度的修饰基因的理解。为了在分子水平上鉴定和表征pcy突变，我们将（1）使用RPCI-23小鼠基因组文库分离BAC重叠群中的最小pcy间隔，以供NIH小鼠基因组测序计划测序;（2）通过系统表征位于我们的pcy间隔内的候选基因来鉴定pcy基因。为了提高我们对调节多囊肾病表型严重程度的修饰基因的理解，我们将（1）使用标记辅助选择育种方法将两个定位的修饰基因座分离到单独的同源株中，和（2）使用基因表达谱对轻度PKD的同类小鼠肾脏和年龄匹配的肾脏中差异表达的基因组进行分类严重PKD的同类小鼠。