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）：我们的长期目标是理解常染色体显性多囊肾脏疾病（ADPKD）的病理生理学作为治疗的基础。常染色体显性多囊性肾脏疾病（ADPKD）是人类最常见的致命单基因遗传疾病，影响了大约1,000名个体中的1个。 ADPKD会导致肾脏组织和进行性肾衰竭的囊性替代，需要在50岁时肾脏替代疗法。这是一种涉及肾脏，肝脏，胰腺，动脉和心脏的全身性疾病。 PKD1和PKD2中的突变几乎引起ADPKD的所有病例。 PKD1和PKD2分别编码Polycystin-1和2（PC1和PC2）。我们最近表明，PC1充当G蛋白耦合受体，PC2充当Ca2+渗透阳离子通道。 PC1和PC2受体通道复合物在流体流动剪应力的机械敏化中起关键作用。我们已经表明，天然PC2在肾上皮细胞中充当Ca2+渗透阳离子选择性离子通道。最近，我们已经显示，PC2通道与PC1结合使用，通过充当膜锚来调节细胞周期的进程，并直接调节转录调节剂ID2的胞质/核易位。该更新建议的主要目的是继续我们对PC2的研究，以了解由多囊这介导的信号通路以及导致囊肿形成的分子机制。我们将专注于5行调查：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的孔区域来产生成年PC2敲除小鼠模型； 3）我们会的确定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窝中发展肾上皮细胞系； 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。这些研究可能会导致可能抑制或治愈ADPKD的新疗法发展。