Identifying Kidney Disease Genes Through Mutagenesis

描述（由申请人提供）：肾脏疾病是美国的主要经济和健康负担。在人类、大鼠和小鼠中的几项研究已经确定了肾脏疾病的遗传成分;然而，已经确定的致病基因相对较少，并且目前用于肾脏疾病研究的动物模型不足。突变是鉴定小鼠致病基因和建立新型小鼠疾病模型的有效方法。我们建议筛选来自杰克逊实验室心脏、肺和血液诱变项目的诱变小鼠，以寻找导致肾脏疾病的突变。我们将筛选第三代后代，使我们能够检测显性和隐性突变。基于我们成功的试点研究，我们预计筛选4500诱变小鼠，以确定45个表型异常，我们预计，其中15-20将传递遗传突变。对于每个新的突变株，我们将把致病突变定位到染色体位置，表征肾脏结构和功能，并建立一个菌落分发给研究界。此外，我们将在克隆至少两种突变株的致病突变方面取得实质性进展。拟议目标的完成将为研究界提供新的、表征良好的肾脏疾病动物模型。拟议中的研究将通过鉴定致病基因在短期内推进我们对肾脏疾病遗传学的认识，并为长期在动物模型中继续研究肾脏疾病提供宝贵的资源。

DESCRIPTION (provided by applicant): Kidney disease is a major economic and health burden in the United States. Several studies, in human , rat, and mouse, have established a genetic component to kidney disease; however, relatively few causal genes have been identified and the current animal models for the study of kidney disease are insufficient . Mutagenesis is an effective method for identifying disease-causing genes in mice and establishing novel murine models of disease. We propose to screen mutagenized mice from the Heart, Lung, and Blood Mutagenesis Program at The Jackson Laboratory for mutations leading to kidney disease. We will screen third generation progeny , enabling us to detect both dominant and recessive mutations . Based on our successful pilot study, we expect to screen 4500 mutagenized mice to identify 45 phenotypic deviants, and we anticipate that 15-20 of these will transmit heritable mutations. For each new mutant strain, we will map the causal mutation to a chromosomal position, characterize renal structure and function , and establish a colony for distribution to the research community. Additionally , we will make substantial progress towards cloning the causal mutation in at least two of the mutant strains. Completion of the proposed aims will provide the research community with new, well-characterized animal models of kidney disease. The proposed research will advance our knowledge of the genetics of kidney disease in the short term by identifying causal genes and provide valuable resources for the continued study of kidney disease in animal models over the long- term.