A New Locus for Hereditary FSGS on Chromosome 2p

描述(由申请人提供)： 研究：局灶性和节段性肾小球硬化(FSGS)是一种重要的临床病理实体，发病率估计为每百万人中有7人。在美国，终末期肾病(ESKD)占所有病例的5%-20%，是儿童ESKD的第二大病因，仅次于泌尿生殖系统和肾脏畸形。FSGS的发病机制尚不清楚。最近对肾病综合征和FSGS中突变的新基因的定位克隆的结果为疾病的发病机制提供了重要的见解，包括FSGS和足细胞之间的强烈联系。最近，申请者在一个有13个患病个体的大家族中定义了FSGS染色体2p上的一个新的基因座。揭示该家族突变的基因将进一步加深我们对FSGS发病机制的理解，并有可能导致对其预防和治疗的合理方法。这项研究的总体目标是使用候选基因策略调查与遗传性FSGS相关的分子缺陷。 具体目标1：对染色体2p上新的FSGS基因座进行精细定位。我们将使用多态标记和单倍型分析来缩小最小候选区域(MCR)。 特定目的2：对染色体2p上的最小候选区域(MCR)进行候选基因分析。MCR中所有合适的基因都将被确定为候选基因，并对突变进行筛选，以确定家族性FSGS家系6543中的致病突变。为了确定基因突变的因果关系，将使用细胞生物学方法和适合基因功能的小鼠模型进行体外和体内功能研究。 候选人：候选人申请K08奖的主要目标是成为FSGS分子发病机制研究中的一名成功和独立的研究员。 环境：这项研究将在杜克大学医学中心最先进的多学科人类遗传学中心进行。杜克大学的肾病学项目有24名教员，他们对临床和研究感兴趣。 这位导师和共同导师是单基因肾脏疾病、血管紧张素、足细胞生物学研究和肾脏疾病小鼠模型方面的知名专家。 公共卫生相关性：本提案中概述的研究将为申请者提供一个出色的培训机会。此外，这项建议中概述的研究将为我们进一步了解家族性FSGS的发病机制和分子基础，以及可能对更常见的特发性FSGS的管理和预防提供进一步的见解。

DESCRIPTION (provided by applicant): Research: Focal and segmental glomerulosclerosis (FSGS) is an important clinicopathologic entity, with an incidence that is estimated at seven per million individuals. It is responsible for 5-20% of all cases of end stage kidney disease (ESKD) in the United States and is second only to urogenital and kidney malformation as a cause of ESKD in children. The pathogenesis of FSGS is not well defined. Recent results from positional cloning of novel genes mutated in nephrotic syndrome and FSGS have provided important insights into the pathogenesis of the disease, including a strong link between FSGS and the podocyte. Recently, the applicant defined a new locus on chromosome 2p for FSGS in a large kindred with 13 affected individuals. Unveiling the gene that is mutated in this family will further our understanding of the pathogenesis of FSGS and has the potential to lead to rational approaches to its prevention and therapy. The overall objective of this study is to investigate the molecular defects associated with an inherited form of familial FSGS using candidate gene strategies. Specific aim 1: To perform fine mapping of the new FSGS locus on chromosome 2p. We will narrow the minimal candidate region (MCR) using polymorphic markers and haplotype analysis. Specific aim 2: To perform candidate gene analysis in the minimal candidate region (MCR) on chromosome 2p. All suitable genes in the MCR will be identified as candidates and screened for mutations to identify the disease-causing mutation in family 6543 with familial FSGS. To establish the causality of the gene mutation, in-vitro and in-vivo functional studies will be performed using cell biology approaches and mouse models appropriate to the function of the gene. The candidate: The candidate's primary goal in applying for a K08 award is to become a successful and independent investigator in the study of the molecular pathogenesis of FSGS. Environment: The study will be carried out in the state-of-the-art multidisciplinary Center for Human Genetics at Duke University Medical Center. The nephrology program at Duke University has 24 faculty with integrated and diverse clinical and research interests. The mentor and co-mentor are known experts in monogenic kidney diseases, angiotensin, podocyte biology research and mouse models of kidney disease. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal will provide an outstanding training opportunity for the applicant. In addition, the studies outlined in this proposal will provide further insight into our understanding of the pathogenetic and molecular basis of familial FSGS and possibly, the management and prevention of the more common idiopathic FSGS.