POLYCYSTIN 1 IN EPITHELIAL CELL DIFFERENTIATION AND CYSTOGENESIS

多囊蛋白 1 在上皮细胞分化和细胞生成中的作用

• 批准号: 6589752
• 负责人: M. AMIN ARNAOUT
• 金额: $ 23.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6589752
• 关键词: apoptosis; cell differentiation; cell proliferation; cellular polarity; epithelium; extracellular matrix; gene expression; kidney; laboratory mouse; membrane proteins; molecular pathology; pathologic process; polycystic kidney; polymerase chain reaction; protein protein interaction; tissue /cell culture

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disease with variable expression that is characterized by cyst formation in ductal organs, principally the kidneys and liver, vascular aneurysms, cardiac valve defects and colonic diverticulae. Genetic studies have linked the defect to at least three loci, and identified two of the genes os PKD1 and PKD2. Biochemical studies associated cyst formation with abnormal epithelial proliferation, polarity and basement membrane composition, features that characterize, features that characterize the less mature epithelium of developing and regenerating kidneys. Polycystin 1, the product of PKD1, is a developmentally- regulated multi-spanning membrane protein with a large extracellular region consisting of a novel mosaic of protein-protein interaction domains. Polycystin 2, the product of PKD2 is a hexaspanner with cytoplasmic N- and C-termini and homology to a voltage-activated calcium channel. The ADPKD phenotype in patients with mutations in PKD1 or PKD2 differs in disease progression and severity but not in the spectrum of the organs involved. This suggests that the respective proteins, in conjunction with other interacting proteins, function as components of a common pathway of epithelial differentiation in which polycystin 1 serves as a sensor, and regulates a putative ion channel activity of polycystin 2. Our goals are to elucidate the elements of this pathway in order to understand its precise role in terminal epithelial differentiation. We will attempt to define the earliest events (cellular processes and genes) affected by the loss of polycystin 1. We also propose to identify extracellular ligands for polycystin 1, and determine how the interaction of its cytoplasmic regions with 14-3-3 proteins is modulated during differentiation. These aims will be addressed using basic biochemical, immunochemical, molecular and cell biology techniques and making use of homozygous and heterozygous polycystin 1 knock out mice. The results of these studies should provide important insights into the mechanisms of epithelial morphogenesis during tabular maturation, identify possible modifiers, and suggest potential targets and approaches for therapeutic intervention that may significantly halt the progression of ADPKD.

常染色体显性遗传性多囊肾病（ADPKD）是一种全身性疾病， 以囊肿为特征的具有可变表达的疾病 形成于导管器官，主要是肾脏和肝脏，血管 动脉瘤、心脏瓣膜缺陷和结肠憩室。遗传 研究表明，这种缺陷至少与三个位点有关， PKD 1和PKD 2基因中的两个。生化研究相关囊肿 形成异常上皮增生、极性和基底 膜组成，表征的特征， 表征发育和再生的不太成熟的上皮 肾脏 多囊蛋白1是PKD 1的产物，是一种发育- 一种受调节的多跨膜蛋白， 由蛋白质-蛋白质相互作用的新镶嵌物组成的区域 域.多囊蛋白2，PKD 2的产物，是一种具有 细胞质N-和C-末端以及与电压激活钙的同源性 频道PKD 1或PKD 2突变患者的ADPKD表型 不同的疾病进展和严重程度，但不是在频谱 涉及的器官。这表明，不同的蛋白质， 与其他相互作用的蛋白质结合，作为 上皮分化的共同途径，其中多囊蛋白1 作为一个传感器，并调节一个假定的离子通道活动， 多囊蛋白2.我们的目标是阐明这一途径的要素， 为了了解其在终末上皮细胞中的确切作用， 分化我们将尝试定义最早的事件（细胞 过程和基因）受到多囊蛋白1的损失的影响。我们也 提出鉴定多囊蛋白1的细胞外配体， 确定其细胞质区域与14-3-3的相互作用 蛋白质在分化过程中受到调节。这些目标将是 使用基本的生物化学、免疫化学、分子和细胞 生物技术和利用纯合子和杂合子 多囊蛋白1基因敲除小鼠。这些研究的结果应该提供 上皮形态发生机制的重要见解 在表格成熟过程中，识别可能的修饰语，并建议 治疗干预的潜在目标和方法， 显著阻止ADPKD的进展。