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（逐字研究来自研究者的摘要）：多囊性肾脏疾病 由一组由突变引起的一组遗传疾病至少5个 遗传上不同的基因。 PKD最常见的常染色体显性形式 多囊性肾脏疾病（ADPKD）是最常见的单基因遗传之一 人类的疾病（PDPKD），影响1,000人中的大约1个。 ADPKD导致 囊性替代肾组织和进行性肾衰竭，需要 肾脏替代疗法在50岁时的一半案件中。这是一种系统性 疾病不仅涉及肾脏，还涉及肝脏，胰腺，动脉 和心。多环芳烃包括一类新的跨膜蛋白。到 日期，四个由四个遗传上不同基因编码的polycystins已经是 确定。 Polycystins -1和-2在常染色体显性中突变 多囊肾脏疾病（ADPKD）。 polycystins -rej和-l，主要是 与polycystin -1和-2密切相关，尚未涉及 在疾病状态。多囊蛋白家族可以分为polycystin-1 （PC1） - 类和polycystin-2（PC2）类似子组。两种PC2状蛋白质 （polycystins -2和-l）与阳离子通道共享结构同源性 瞬态受体电位（TRP）和电压门控Ca2+，Na+和 K+渠道家庭。另一方面，两个PC1样分子，Polycystins-1 和-rej，与推定离子共享重要的领域和序列同源 海胆中的通道调节剂（鸡蛋果冻的受体）。这个对象 更新建议是扩展polycystin -1和 polycystin-l。将进行三个主要调查。首先，进一步 表征两个先前确定的潜在结合伙伴的表征 polycystin-1，并继续搜索polycystin-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 并确定其他多囊体（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 靶向实验以阐明多囊这在 体内。