Molecular pathophysiology of Pkd2 mutations

描述（由申请人提供）：我们的长期目标是了解常染色体显性多囊肾病（ADPKD）的病理生理学，作为治疗的基础。常染色体显性遗传性多囊肾病（ADPKD）是人类最常见的致死性单基因遗传病，约1/1，000的个体受到影响。ADPKD导致肾组织囊性替代和进行性肾衰竭，50岁时一半病例需要肾脏替代治疗。它是一种涉及肾脏、肝脏、胰腺、动脉和心脏的全身性疾病。PKD 1和PKD 2的突变导致几乎所有ADPKD病例。PKD 1和PKD 2分别编码多囊蛋白1和2（PC 1和PC 2）。我们最近发现，PC 1作为一个G-蛋白偶联受体和PC 2作为一个Ca 2+渗透性阳离子通道的功能。PC 1和PC 2受体通道复合体在流体流动剪切应力的机械感觉中起关键作用。我们已经表明，本地PC 2功能作为一个Ca 2+渗透性阳离子选择性离子通道在肾上皮细胞。最近，我们已经表明，PC 2通道，与PC 1，调节细胞周期的进程，作为一个膜锚，并直接调节Id 2，转录调节胞质/核易位。这项更新建议的主要目的是继续我们对PC 2的研究，以了解多囊蛋白介导的信号通路和导致囊肿形成的分子机制。我们将集中在5个方面的研究：1）我们将表征我们最近产生的种系Pkd 2敲除小鼠; 2）我们将通过破坏PC 2的孔区域来产生成年PC 2敲除小鼠模型; 3）我们将 确定PC 2-ld 2相互作用的生理学意义; 4）我们将从Pkd 2突变体及其野生型同窝仔开发肾上皮细胞系; 5）我们将研究PC 2突变对细胞和体内PC 2介导的信号传导途径的影响。这些研究可能会导致可能缓解或治愈ADPKD的疗法的新发展。

DESCRIPTION (provided by applicant): Our long-term objective is ,to understand the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD) as a basis for therapy. Autosomal dominant polycystic kidney disease (ADPKD) is the most common lethal monogenic genetic diseases of man, affecting approximately 1 in 1,000 individuals. ADPKD leads to cystic replacement of renal tissue and progressive renal failure, requiring renal replacement therapy in half of the cases by age 50. It is a systemic disease involving the kidney, liver, pancreas, arteries and the heart. Mutations in PKD1 and PKD2 cause almost all cases of ADPKD. PKD1 and PKD2 encode polycystin-1and-2 (PC1 and PC2), respectively. We have recently shown that PC1 acts as a G-protein coupled receptor and PC2 functions as a Ca2+permeable cation channel. PC1 and PC2 receptor channel complex play a critical role in mechanosensation of fluid flow shear stress. We have shown that native PC2 functions as a Ca2+ permeable cation selective ion channel in renal epithelial cells. Mostly recently, we have shown that PC2 channel, in concert with PC1, regulates cell cycle progression by serving as a membrane anchor and directly regulates the cytosol/nuclear translocation of Id2, a transcription regulator. The major object of this renewal proposal is to continue our studies on PC2 to understand the signaling pathways mediated by polycystins and the molecular mechanisms leading to cyst formation. We will focus on 5 lines of investigation: 1) we will characterize a germline Pkd2 knockout mice we recently generated; 2) we will generate adult PC2 knockout mouse models by disrupting the pore region of PC2; 3) we will determine the physiological significance of PC2-ld2 interaction; 4) we will develop kidney epithelial cell lines from Pkd2 mutants and their wild type littermates; 5) we will study the effect of PC2 mutation on PC2 mediated signaling pathway in cells and in vivo. These studies are likely to lead to new developments of therapies that may palliate or cure ADPKD.