Cell biology of autosomal dominant polycystic kidney disease

常染色体显性多囊肾病的细胞生物学

基本信息

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
项目类别：
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

项目摘要

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）：主要的纤毛，现在被称为感官细胞器和几乎所有细胞中存在的信号传导中心，在过去的十年中，由于其在具有囊性肾脏表型的大量疾病中的作用而引起了很多关注。基因耗竭和缺失实验，人类遗传学表明，肾上皮细胞原发性纤毛中的结构或功能缺陷会导致囊肿的形成。现在，人类疾病的成长组为纤毛缺陷和表型，包括囊性肾脏，肥胖，失明和智力低下，现在被统称为纤毛病。常染色体显性多囊性肾脏疾病（ADPKD）是最常见的纤毛病，一直是我实验室的长期研究重点。关于ADPKD的大多数研究都集中在PC1蛋白的损失如何导致ADPKD中的许多细胞缺陷上，尽管大量ADPKD谱系具有突变，从而导致突变蛋白到其正常功能部位的有缺陷。目前，关于膜蛋白的结构决定因素知之甚少，该膜蛋白可以传播到原发性纤毛和此过程所需的细胞机械。全长PC1运输到主要纤毛的机制尚不清楚。我们建议阐明PC1运输到主要纤毛的机制对于理解PC1功能和ADPKD的发病机理以及ADPKD的治疗剂设计至关重要。我们设计了两个目标。 AIM 1：阐明PC1中负责对原发性纤毛的靶向的结构决定因素； AIM 2：确定用于PC1运输到睫状膜的机械。