Harvard Center of Polycystic Kidney Disease Research

哈佛大学多囊肾病研究中心

• 批准号: 7035219
• 负责人: Jing Zhou
• 金额: $ 113.3万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7035219
• 关键词: pathologic process; polycystic kidney

Polycystic kidney disease (PKD) is a common genetic disease that is characterized by the development of fluid filled cysts in the kidney and is associated with high morbidity and mortality. Autosomal dominant PKD (ADPKD) affects approximately 1:1000 individuals, whereas autosomal recessive PKD (ARPKD) is seen in approximately 1:20,000 live births. The molecular mechanisms underlying cyst formation remain unclear. The recent work from the Director's laboratory has shown that polycystin-1 and -2 function as a receptor channel complex that mediates G protein and calcium signaling and mechanosensation. The director has developed a number of mouse models with mutations in the mouse ortholog of the human ADPKD gene and generated cell lines from these mouse mutants and their wild type littermates. Taking advantage of these and other reagents developed in the Director's laboratory, the Center investigators will explore the molecular mechanisms underling human polycystic kidney disease. Project 1 (Dr. Denker) will use biochemical, cell biological and genetic approaches to understand the role of heterotrimeric G proteins in PKD. In Project 2 Dr. Kreidberg will use a combination of cell and molecular bioiogical approaches to understand the role of cadherins and integrins in the pathogenesis of polycystic kidney disease. In Project 3 Dr. Zhou will use biochemical and cell biological approaches to understand the role of fibrocystin/polyductin (FPC) in comparison with the roles of polycystins in PKD. Each of these projects will be supported by a Core facility that will provide most up to date support on molecular imaging and an administrative Core. The proposed studies are highly relevant to both the recessive and dominant forms of human polycystic kidney disease. Results from these studies will advance our understanding of the molecular mechanisms underlying cystogenesis and lead to the identification of novel therapeutic strategies.

多囊肾病（PKD）是一种常见的遗传性疾病，其特征是肾脏中出现充满液体的囊肿，发病率和死亡率很高。常染色体显性 PKD (ADPKD) 影响大约 1:1000 的个体，而常染色体隐性 PKD (ARPKD) 则影响大约 1:20,000 的活产儿。囊肿形成的分子机制仍不清楚。主任实验室最近的工作表明，多囊蛋白-1 和-2 作为受体通道复合物发挥作用，介导 G 蛋白和钙信号传导以及机械感觉。该主任开发了许多带有人类 ADPKD 基因小鼠直系同源突变的小鼠模型，并从这些小鼠突变体及其野生型同窝小鼠中产生了细胞系。利用主任实验室开发的这些试剂和其他试剂，中心研究人员将探索人类多囊肾病的分子机制。项目 1（Denker 博士）将使用生物化学、细胞生物学和遗传学方法来了解异源三聚体 G 蛋白在 PKD 中的作用。在项目 2 中，Kreidberg 博士将结合使用细胞和分子生物学方法来了解钙粘蛋白和整合素在多囊肾疾病发病机制中的作用。在项目 3 中，周博士将使用生化和细胞生物学方法来了解纤囊蛋白/多导蛋白 (FPC) 与多囊蛋白在 PKD 中的作用的比较。这些项目中的每一个都将得到核心设施的支持，该设施将提供分子成像和管理核心的最新支持。 拟议的研究与人类多囊肾病的隐性和显性形式高度相关。这些研究的结果将增进我们对囊肿发生分子机制的理解，并导致新的治疗策略的确定。