Identifying Kidney Disease Genes Through Mutagenesis

描述(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、大鼠和小鼠身上进行的几项研究已经确定了肾脏疾病的遗传成分；然而，相对较少的原因基因被识别出来，并且目前用于肾脏疾病研究的动物模型是不够的。突变是鉴定小鼠致病基因和建立新的小鼠疾病模型的有效方法。我们建议从杰克逊实验室的心、肺和血液突变计划中筛选突变小鼠，以寻找导致肾脏疾病的突变。我们将筛查第三代后代，使我们能够检测到显性和隐性突变。基于我们成功的初步研究，我们预计将筛选4500只突变小鼠，以识别45个表型变异，我们预计其中15-20个将传播可遗传突变。对于每个新的突变株，我们将把原因突变映射到染色体位置，表征肾脏结构和功能，并建立一个菌落分配给研究社区。此外，我们将在克隆至少两个突变菌株的因果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、具有良好特征的肾脏疾病动物模型。这项拟议的研究将在短期内通过识别致病基因来促进我们对肾脏疾病遗传学的了解，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.