中国人局灶节段肾小球硬化症致病基因INF2突变及功能研究

项目名称： 中国人局灶节段肾小球硬化症致病基因INF2突变及功能研究

项目编号： No.81200488

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 马骏

作者单位： 上海交通大学

项目金额： 24万元

中文摘要： 局灶节段性肾小球硬化症（FSGS）是国人最常见的原发性肾小球肾炎之一，临床主要表现为中到大量蛋白尿。其病因不明，患者对现有药物治疗不敏感导致肾功能不断恶化进入终末期肾病。目前认为遗传因素参与FSGS发病，特别是近期发现的编码反转成蛋白-2(inverted formin 2)的基因INF2突变在FSGS发病中起重要作用，但机制有待深入研究。我们前期共收集迟发性FSGS家系91个，散发患者900余例，开展过致病基因ACTN4、TRPC6的筛查和功能研究。最近对部分FSGS家系患者筛查中又发现了INF2新突变位点。本研究将在此工作基础上继续在家系及部分原发FSGS患者中筛查INF2基因突变，并选取发现的突变位点采用构建质粒、定点诱变、细胞转染、免疫组化、共聚焦显微镜等技术于体内外分别在细胞、分子和组织水平进行功能研究。以期明确INF2突变在国人FSGS发病中的作用，并在致病机制研究中取得突破。

中文关键词： 局灶节段肾小球硬化症；反转蛋白2；基因突变；足细胞；功能研究

英文摘要： Focal segmental glomerulosclerosis (FSGS) is one of the most common primary glomerulonephritis in Chinese patients. The major clinical manifestations is moderate to massive proteinuria. A considerable portion of the patients is insensitive or resistant to steroid and immunosuppressive therapy and progress to end stage renal failure, and eventually require renal replacement therapy,such as hemodialysis or kidney transplantation. Previous study indicated that the genetic background was involved in the incidence of FSGS. And recently INF 2 gene(encoding inverted formin 2) mutations were confirmed to be the major cause of autosomal dominant inherited FSGS and also play an important role in the pathogenesis of the sporadic FSGS. But the exact mechanism remains to be elucidated. We have collected ninety-one late onset FSGS families , and more than nine hundred cases of sporadic FSGS patients during the past fifteen years. We also carried out the screening and functional studies for some of the pathogenic genes cause familial FSGS. Recnetly, we sequenced the INF2 gene on the part of the familial FSGS patients and identified two novel pathogenic mutations. Based on the fundamental work, we will continue the INF2 gene mutation screening work in the remanent familial FSGS patients and also in the steroid-resistant pri

英文关键词： focal segmental glomerulosclerosis；inverted formin2；mutation；podocyte；functional study