Molecular pathophysiology of Pkd2 mutations

Pkd2 突变的分子病理生理学

基本信息

批准号：
7919198
负责人：
Jing Zhou
金额：
$ 10.08万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2010-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919198
关键词：
Adult Affect Age Animal Model Architecture Autosomal Dominant Polycystic Kidney Binding Breeding C-terminal Cations Cell Culture Techniques Cell Cycle Cell Cycle Progression Cell Cycle Regulation Cell Line Cell Polarity Cells Cilia Complex Coronary artery Cultured Cells Cyst Cytosol Development Disease Doctor of Medicine Doctor of Philosophy Dose Epithelial Cells Epithelium Exons Failure Fetal Development Functional disorder Funding G-Protein-Coupled Receptors GTP-Binding Proteins Gene Targeting Genes Genetic Transcription Hereditary Disease Homologous Gene Human Individual Investigation Ion Channel Kidney Kidney Failure Knock-out Knockout Mice Lead Life Liver Longitudinal Studies Maintenance Mediating Membrane Methodology Modeling Molecular Mus Mutant Strains Mice Mutation Nature Neonatal Nuclear Translocation PKD2 protein Pancreas Patients Phenotype Physiological Play Proprotein Convertase 1 Proprotein Convertase 2 Proteins Reagent Renal Replacement Therapy Renal Tissue Reporter Research Personnel Role Signal Pathway Signal Transduction Staging Study models Systemic disease Testing Tissues Transcript Tube Tubular formation base disease-causing mutation fluid flow improved in vivo kidney cell kidney epithelial cell man mouse model mutant novel postnatal prevent programs promoter receptor recombinase shear stress therapeutic target therapy development

项目摘要

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.

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。常染色体显性多囊肾病 (ADPKD) 是人类最常见的致命性单基因遗传病，影响大约千分之一的人。 ADPKD 会导致肾组织囊性替代和进行性肾功能衰竭，一半的病例在 50 岁时需要进行肾脏替代治疗。它是一种涉及肾脏、肝脏、胰腺、动脉和心脏的全身性疾病。几乎所有 ADPKD 病例都是由 PKD1 和 PKD2 突变引起。 PKD1 和 PKD2 分别编码多囊蛋白-1 和-2（PC1 和 PC2）。我们最近证明 PC1 作为 G 蛋白偶联受体，而 PC2 作为 Ca2+ 渗透性阳离子通道。 PC1 和 PC2 受体通道复合体在流体流动剪切应力的机械感觉中发挥着关键作用。我们已经证明，天然 PC2 在肾上皮细胞中起到 Ca2+ 渗透性阳离子选择性离子通道的作用。最近，我们发现 PC2 通道与 PC1 协同作用，通过充当膜锚来调节细胞周期进程，并直接调节转录调节因子 Id2 的胞质/核易位。这项更新提案的主要目的是继续我们对 PC2 的研究，以了解多囊蛋白介导的信号通路以及导致囊肿形成的分子机制。我们将重点研究 5 个方向：1）我们将表征我们最近生成的种系 Pkd2 敲除小鼠； 2）我们将通过破坏PC2的孔区域来生成成年PC2敲除小鼠模型； 3）我们会确定 PC2-ld2 相互作用的生理意义； 4）我们将从Pkd2突变体及其野生型同窝培养肾上皮细胞系； 5）我们将研究PC2突变对细胞和体内PC2介导的信号通路的影响。这些研究可能会带来缓解或治愈 ADPKD 疗法的新进展。