Harvard Center of Polycystic Kidney Disease Research

多囊肾病(PKD)是一种常见的遗传性疾病，以肾脏内充满液体的囊性病变为特征，具有较高的发病率和死亡率。常染色体显性遗传性PKD(ADPKD)的发病率约为1：1000，而常染色体隐性遗传性PKD(ARPKD)的发病率约为1：20,000。包囊形成的分子机制尚不清楚。主任实验室最近的工作表明，多囊蛋白-1和-2作为一种受体通道复合体，介导G蛋白和钙信号和机械感觉。这位主任已经开发了一些带有人类ADPKD基因的小鼠同源突变的小鼠模型，并从这些小鼠突变体和它们的野生型窝胎中产生了细胞系。利用主任实验室开发的这些试剂和其他试剂，中心的研究人员将探索人类多囊肾病的分子机制。项目1(Denker博士)将使用生化、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博士将使用细胞和分子生物方法的组合来了解钙粘附素和整合素在多囊肾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维囊藻毒素/多聚管蛋白(FPC)的作用，并与多囊蛋白在PKD中的作用进行比较。这些项目中的每一个都将得到一个核心设施的支持，该设施将提供分子成像方面的最新支持和一个管理核心。 拟议的研究与人类多囊肾病的隐性和显性形式都高度相关。这些研究的结果将促进我们对囊变发生的分子机制的理解，并导致新的治疗策略的确定。

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.