MOLECULAR PATHOLOGY OF POLYCYRSTIC KIDNEY DISEASE

多囊肾疾病的分子病理学

• 批准号: 6127464
• 负责人: Jing Zhou
• 金额: $ 35.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6127464
• 关键词: MDCK cell; RNase protection assay; SDS polyacrylamide gel electrophoresis; Xenopus oocyte; autosomal dominant trait; electrophysiology; gene expression; gene mutation; gene targeting; genetic techniques; genetically modified animals; genotype; immunoprecipitation; in situ hybridization; laboratory mouse; linkage mapping; membrane proteins; molecular cloning; molecular pathology; polycystic kidney; polymerase chain reaction; protein binding; protein protein interaction; protein structure function; voltage gated channel; yeast two hybrid system

DESCRIPTION (Verbatim from Investigator's Abstract): Polycystic kidney disease comprises a group of genetic disorders caused by mutations in at least 5 genetically distinct genes. The most common form of PKD, autosomal dominant polycystic kidney disease (ADPKD), is one of the most common monogenic genetic diseases (PDPKD) of man, affecting about 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 not only the kidney but also the liver, pancreas, arteries and heart. Polycystins comprise a new class of membrane-spanning proteins. To date, four polycystins, encoded by four genetically distinct genes, have been identified. Polycystins -1, and -2, are mutated in autosomal dominant polycystic kidney disease (ADPKD). Polycystins-REJ and -L, which are mostly closely related to polycystin -1 and -2, respectively, are not yet implicated in disease states. The polycystin family can be divided into polycystin-1 (PC1)-like and polycystin-2(PC2)-like subgroups. Both PC2-like proteins (polycystins-2 and -L) share structural homology with cation channels such as those of the transient receptor potential (TRP) and voltage-gated Ca2+, Na+ and K+ channel families. On the other hand, both PC1-like molecules, polycystins-1 and -REJ, share significant domain and sequence homology to a putative ion channel regulator (receptor for egg jelly) in sea urchins. The object of this renewal proposal is to extend the functional studies of polycystin -1 and polycystin-L. Three main lines of investigation will be pursued. First, further characterization of two previously identified potential binding partners of polycystin-1, and continue to search for polycystin-1 ligands. Second, extending the recent studies that show that polycystin-L has channel properties and determine whether other polycystins (1 and 2) modulate these properties. Lastly, complement these biochemical and biophysical studies with gene targeting experiments to elucidate the biological functions of polycystin-L in vivo.

描述（逐字摘自研究者摘要）：多囊肾病 包括一组由至少 5 种基因突变引起的遗传性疾病 遗传上不同的基因。 PKD 最常见的形式，常染色体显性遗传 多囊肾病（ADPKD）是最常见的单基因遗传性疾病之一 人类疾病（PDPKD），影响大约千分之一的人。 ADPKD 导致 肾组织囊性替代和进行性肾衰竭，需要 到 50 岁时，一半病例接受肾脏替代治疗。这是一种全身性治疗 疾病不仅涉及肾脏，还涉及肝脏、胰腺、动脉 和心。多囊蛋白包含一类新的跨膜蛋白。到 迄今为止，由四个遗传上不同的基因编码的四种多囊蛋白已被 确定。多囊蛋白 -1 和 -2 在常染色体显性遗传中发生突变 多囊肾病（ADPKD）。多囊蛋白-REJ和-L，主要是 分别与多囊蛋白-1和-2密切相关，尚未涉及 在疾病状态下。多囊蛋白家族可分为多囊蛋白-1 (PC1) 样和多囊蛋白-2(PC2) 样亚组。两种 PC2 样蛋白 （多囊蛋白-2 和 -L）与阳离子通道具有结构同源性，例如 瞬时受体电位 (TRP) 和电压门控 Ca2+、Na+ 和 K+频道家族。另一方面，PC1 样分子，多囊蛋白-1 和-REJ，与推定离子共享重要的结构域和序列同源性 海胆的通道调节器（蛋冻受体）。本次的对象 更新提案是扩展多囊蛋白-1和的功能研究 多囊蛋白-L。将开展三个主要调查工作。首先，进一步 先前确定的两个潜在结合伙伴的表征 多囊蛋白-1，并继续寻找多囊蛋白-1配体。第二， 扩展了最近的研究，表明多囊蛋白-L 具有通道特性 并确定其他多囊蛋白（1 和 2）是否调节这些特性。 最后，用基因补充这些生化和生物物理研究 靶向实验阐明多囊蛋白-L 的生物学功能 体内。