The Role of CD2AP in Human Glomerular Disease

CD2AP 在人类肾小球疾病中的作用

• 批准号: 7084680
• 负责人: Andrey S. Shaw
• 金额: $ 22.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7084680
• 关键词: African American; HIV infections; cell line; clinical research; disease /disorder etiology; family genetics; gene expression; gene frequency; gene mutation; genetic polymorphism; genetic screening; genetic susceptibility; genetically modified animals; glomerulosclerosis; human genetic material tag; human population genetics; laboratory mouse; membrane proteins; molecular pathology; pathologic process; protein structure function; sign /symptom; transfection

DESCRIPTION (provided by applicant): CD2AP is an 80 KD protein that was cloned as a protein involved in T cell activation. CD2AP also plays a major role in the kidney. CD2AP knockout mice are born with congenital nephritic syndrome and CD2AP is expressed in the glomerular epithelial cell or podocyte. Our previous work suggests that CD2AP plays a critical role in maintaining the integrity of the slit diaphragm, a structure that is critical in the glomerular filtration apparatus. Recently, we discovered that our CD2AP heterozygous mice demonstrate an increased susceptibility to renal injury caused by nephrotoxic antibodies or when bred to the NZB mouse. This suggested that CD2AP heterozygosity might play a role in human glomerular disease. In our preliminary work, we have identified human patients with the diagnosis of focal segmental glomerulosclerosis who are heterozygous for CD2AP. In this grant application, we propose to extend these studies by analyzing a larger population of patients with FSGS for mutations in CD2AP. In the first two aims, we propose to identify genetic variants of CD2AP and determine their prevalence in the population. In aim #3, we propose a series of experiments to determine whether these mutations are disease causing, by testing mutated forms of CD2AP biochemically, by their ability to reconstitute function after transfection in CD2AP deficient cell lines and by their ability to rescue the renal phenotype of the knockout mouse. We hope that these studies lead to new insights into diseases of the glomerulus.

描述（由申请人提供）：CD2AP是80 kD蛋白，克隆为参与T细胞激活的蛋白质。 CD2AP在肾脏中也起着重要作用。 CD2AP基因敲除小鼠出生于先天性肾脏综合征，CD2AP在肾小球上皮细胞或足细胞中表达。我们以前的工作表明，CD2AP在维持狭缝隔膜的完整性方面起着至关重要的作用，该结构在肾小球滤过设备中至关重要。 最近，我们发现我们的CD2AP杂合小鼠表现出增加了由肾毒性抗体引起的肾损伤的敏感性，或者当繁殖到NZB小鼠时。这表明CD2AP杂合性可能在人肾小球疾病中起作用。在我们的初步工作中，我们已经确定了患有局灶性节段性肾小球硬化的局灶性肾小球肾小球的患者，这些患者是CD2AP的杂合子。 在此赠款应用中，我们建议通过分析较大的FSG患者的CD2AP突变患者来扩展这些研究。在前两个目标中，我们建议识别CD2AP的遗传变异，并确定其在人群中的患病率。在AIM＃3中，我们提出了一系列实验，以通过在CD2AP缺陷细胞系中转染后重新构染后重新构建功能的能力来确定这些突变是否是疾病引起的，并通过营救小鼠的肾脏表型。我们希望这些研究能够为肾小球疾病提供新的见解。