A New Locus for Hereditary FSGS on Chromosome 2p

染色体 2p 上遗传性 FSGS 的新位点

• 批准号: 8311730
• 负责人: Rasheed Adebayo Gbadegesin
• 金额: $ 14.48万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8311730
• 关键词: Academic Medical Centers; Actinin; Adult; Affect; Angiotensins; Award; Binding; Biology; Candidate Disease Gene; Cells; Cellular biology; Child; Childhood; Chromosomes; Clinical Research; Defect; Disease; Dominant Genes; End stage renal failure; Environment; Etiology; Event; Faculty; Family; Focal Segmental Glomerulosclerosis; Gene Expression; Gene Mutation; Generations; Genes; Genitourinary system; Genome; Genotype; Goals; Grant; Haplotypes; Health; Histologic; Human; Human Genetics; Immunofluorescence Immunologic; Immunoprecipitation; In Situ Hybridization; In Vitro; Incidence; Individual; Inherited; Kidney; Kidney Diseases; Laboratories; Lead; Link; Maps; Meiosis; Mentors; Methods; Microsatellite Repeats; Molecular; Mutate; Mutation; NPHS2 protein; Nephrology; Nephrotic Syndrome; Pathogenesis; Phenotype; Physicians; Polymorphic Microsatellite Marker; Positioning Attribute; Prevalence; Prevention; Prevention therapy; Principal Investigator; Proteins; Renal glomerular disease; Research; Research Personnel; Resources; Spatial Distribution; Steroid Resistance; Steroids; Testing; Training; Transfection; United States; Universities; Variant; Work; base; cohort; disease-causing mutation; experience; gene function; genome wide association study; genome-wide; in vivo; insight; interest; kindred; malformation; mouse model; multidisciplinary; nephrin; novel; podocyte; positional cloning; programs; protein distribution; research study

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.

描述（由申请人提供）： 研究：局灶性和分段肾小球硬化（FSG）是重要的临床病理学实体，其发病率估计为每百万个个体七个。它负责美国所有终阶段肾脏疾病（ESKD）的5-20％，仅次于泌尿生殖器和肾脏畸形作为儿童ESKD的原因。 FSG的发病机理不是很好的定义。在肾病综合征和FSG中突变的新基因的位置克隆的最新结果为疾病的发病机理提供了重要的见解，包括FSGS与足细胞之间的牢固联系。最近，申请人在与13个受影响的个体的大型亲属中定义了FSG染色体2p染色体的新基因座。揭示该家族中突变的基因将进一步了解FSG的发病机理，并有可能导致其预防和治疗的理性方法。这项研究的总体目的是研究使用候选基因策略与遗传形式的家族性FSG相关的分子缺陷。 特定目标1：在2p染色体上进行新的FSGS基因座的精细映射。我们将使用多态标记和单倍型分析范围缩小最小候选区域（MCR）。 特定目标2：在染色体2p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鉴定为候选物，并筛选出突变，以鉴定与家族性FSG的家族6543中引起疾病​​的突变。为了建立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：申请K08奖的候选人的主要目标是在研究FSG的分子发病机理方面成为成功且独立的研究者。 环境：该研究将在杜克大学医学中心的最先进的人类遗传学中心进行。杜克大学的肾脏科学计划有24名教职员工，具有综合和多样化的临床和研究兴趣。 导师和同事是单基因肾脏疾病，血管紧张素，足细胞生物学研究和肾脏病小鼠模型的知名专家。 公共卫生相关性：该提案中概述的研究将为申请人提供出色的培训机会。此外，该提案中概述的研究将进一步了解我们对家族性FSG的致病性和分子基础的理解，以及更常见的特发性FSG的管理和预防。