Cell biology of autosomal dominant polycystic kidney disease

常染色体显性多囊肾病的细胞生物学

• 批准号: 8698080
• 负责人: Jing Zhou
• 金额: $ 26.54万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-02 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698080
• 关键词: Affect; Alleles; Amino Acid Substitution; Attention; Autosomal Dominant Polycystic Kidney; Bardet-Biedl Syndrome; Biochemical; Biological Assay; Blindness; C-terminal; Cell Line; Cells; Cellular biology; Chemicals; Cilia; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Complex; Cyst; Cystic Kidney Diseases; Cystic kidney; Data; Defect; Disease; Drug Targeting; Effectiveness; Endoplasmic Reticulum; Enzymes; Failure; Family; Foundations; GTPase-Activating Proteins; Genes; Genomics; Glucosidase II; Health; Human; Human Genetics; Image; Individual; Integral Membrane Protein; Kidney Failure; Laboratories; Lead; Length; Liver diseases; Mediator of activation protein; Membrane; Membrane Protein Traffic; Membrane Proteins; Mental Retardation; Missense Mutation; Monomeric GTP-Binding Proteins; Mus; Mutation; Obesity; Organelles; Pathogenesis; Phenotype; Photoreceptors; Polycystic Kidney Diseases; Process; Proprotein Convertase 1; Proprotein Convertase 2; Proteins; Quality Control; Research; Rhodopsin; Role; Sensory; Signal Transduction; Site; System; Tail; Technology; Test Result; Therapeutic; United States; base; ciliopathy; design; genetic pedigree; human disease; in vivo; insight; kidney epithelial cell; member; mutant; novel; polycystic kidney disease 1 protein; protein complex; renal epithelium; research study; small molecule; tool; trafficking

DESCRIPTION (provided by applicant): The primary cilium, now known as a sensory organelle and a signaling center present in almost all cells, has attracted much attention in the past decade due to its role in a large group of diseases with cystic kidney phenotype. Gene depletion and deletion experiments, and human genetics have shown that either a structural or a functional defect in the primary cilium of kidney epithelial cells leads to cyst formation. The growing group of human diseases with ciliary defects and phenotypes including cystic kidneys, obesity, blindness and mental retardation, are now collectively regarded as ciliopathies. Autosomal dominant polycystic kidney disease (ADPKD), the most common form of ciliopathy, has been a long-standing research focus of my lab. Most studies on ADPKD have focused on how loss of PC1 protein leads to a number of cellular defects in ADPKD though a large number of ADPKD pedigrees have mutations that lead to defective targeting of the mutant proteins to their normal functional sites. At present little is known about the structural determinants for membrane proteins to traffic to the primary cilia and the cellular machinery required for this process. Mechanisms by which full-length PC1 traffics to the primary cilium are unknown. We propose that elucidating the mechanisms by which PC1 traffics to the primary cilia is central to understanding PC1 function and the pathogenesis of ADPKD, as well as to the design of therapeutics for ADPKD. We have designed two aims. Aim 1: Elucidate the structural determinants in PC1 responsible for its targeting to the primary cilia; Aim 2: Determine the machinery used for PC1 trafficking to the ciliary membrane.

描述（由申请人提供）：初级纤毛，现在被称为感觉细胞器和存在于几乎所有细胞中的信号中心，由于其在一大组具有囊性肾表型的疾病中的作用，在过去十年中引起了广泛关注。基因缺失和删除实验以及人类遗传学已经表明，肾上皮细胞的初级纤毛中的结构或功能缺陷导致囊肿形成。越来越多的具有纤毛缺陷和表型的人类疾病，包括囊性肾、肥胖、失明和精神发育迟滞，现在被统称为纤毛病。常染色体显性遗传性多囊肾病（ADPKD），最常见的纤毛病变形式，一直是我实验室的长期研究重点。大多数关于ADPKD的研究都集中在PC 1蛋白的缺失如何导致ADPKD中的许多细胞缺陷，尽管大量ADPKD家系具有突变，导致突变蛋白无法靶向其正常功能位点。目前对膜蛋白运输到初级纤毛的结构决定因素和这一过程所需的细胞机制知之甚少。全长PC 1交通的主要纤毛的机制是未知的。我们建议，阐明PC 1交通的主要纤毛的机制是理解PC 1的功能和ADPKD的发病机制，以及ADPKD的治疗设计的核心。我们设定了两个目标。目标1：阐明PC 1负责其针对初级纤毛的结构决定因素;目的2：确定用于PC 1运输到睫状膜的机器。