A New Locus for Hereditary FSGS on Chromosome 2p

描述（由申请人提供）： 调研：局灶节段性肾小球硬化症（FSGS）是一种重要的临床病理实体，其发病率估计为百万分之七。在美国，它占所有终末期肾病（ESKD）病例的5-20%，是仅次于泌尿生殖系统和肾脏畸形的儿童ESKD病因。FSGS的发病机制尚未明确。最近的结果从定位克隆的新基因突变的肾病综合征和FSGS提供了重要的见解，疾病的发病机制，包括FSGS和足细胞之间的强有力的联系。最近，申请人在具有13个受影响个体的大家族中定义了染色体2 p上的FSGS新基因座。揭示该家族中发生突变的基因将进一步加深我们对FSGS发病机制的理解，并有可能导致合理的预防和治疗方法。本研究的总体目标是利用候选基因策略研究与家族性FSGS遗传形式相关的分子缺陷。 具体目标1：在染色体2 p上进行新的FSGS基因座的精细定位。我们将缩小最小候选区域（MCR）使用多态性标记和单倍型分析。 具体目标2：在染色体2 p上的最小候选区域（MCR）中进行候选基因分析。MCR中的所有合适基因将被确定为候选基因，并筛选突变，以确定家族性FSGS家族6543中的致病突变。为了确定基因突变的因果关系，将使用适合基因功能的细胞生物学方法和小鼠模型进行体外和体内功能研究。 候选人：候选人申请K 08奖的主要目标是成为FSGS分子发病机制研究中成功和独立的研究者。 环境：本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。杜克大学的肾脏病学项目有24名教师，他们具有综合和多样化的临床和研究兴趣。 导师和共同导师是单基因肾病、血管紧张素、足细胞生物学研究和肾病小鼠模型方面的知名专家。

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.