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Endocytic Pathway Dysfunction in Dent Disease

马齿病中的内吞途径功能障碍

基本信息

批准号：
10597036
负责人：
Ora A Weisz
金额：
$ 47.2万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-10 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597036
关键词：
Acute Affect Albumins Apical Binding Biochemical CRISPR/Cas technology Cell Culture Techniques Cells Cholesterol Chronic Chronic Kidney Failure Clinical Cystinosis DNA Sequence Alteration Defect Degradation Pathway Dent Disease Development Diabetes Mellitus Didelphidae Disease Disputes Early Endosome End stage renal failure Endocytosis Endosomes Excretory function Functional disorder Genes Genetic Genetic Diseases Genetic Transcription Glycogen Synthase Kinase 3 Heavy Metals Homeostasis Image Impairment Injury to Kidney Ion Transport Ions Kidney Kinetics Knock-out Knockout Mice LDL-Receptor Related Protein 2 Ligands Link Lysosomes Medicare Membrane Protein Traffic Modeling Molecular Molecular Weight Morphology Mus Mutate Mutation Nephrons Oculocerebrorenal Syndrome PPAR alpha Pathogenesis Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Persons Prevalence Proteins Proteinuria Proximal Kidney Tubules Recovery Recycling Research Risk Route System Testing Therapeutic Intervention Transplantation Treatment Cost Tubular formation United States Urine aging population apical membrane design disease phenotype effective therapy experimental study glomerular filtration inhibitor intrinsic factor-cobalamin receptor kidney cell kidney dysfunction knock-down mathematical model metal poisoning mouse model mutant novel prevent receptor receptor binding restoration therapeutic target therapy design trafficking uptake urinary

项目摘要

Abstract Tubular proteinuria resulting from impaired endocytic uptake of filtered proteins by the kidney proximal tubule (PT) is a common feature of early kidney dysfunction that poses a significant risk for development of end-stage renal disease. This proposal aims to understand the mechanistic basis of Dent disease, a progressive genetic disorder characterized by tubular proteinuria that is caused by mutations in the 2Cl-/H+ exchanger ClC-5. Enhanced degradation of megalin, a multiligand co-receptor that binds to filtered proteins, is thought to underlie the tubular proteinuria in Dent disease, however, the step in trafficking that is affected is unknown, and the contribution of pH vs. Cl- homeostasis to the disease phenotype is disputed. We will utilize a combination of genetic, morphological, mathematical modeling, and biochemical approaches to accomplish the following aims: (1) identify the step(s) in membrane traffic that are impaired in ClC-5 knockdown PT cells; (2) determine the molecular mechanism that links loss of ClC-5 to reduced megalin expression; and (3) identify therapeutic targets for restoring megalin expression and function in a mouse model of Dent disease.

抽象的由于肾脏对过滤蛋白的内吞摄取受损而导致的管状蛋白尿近端小管（PT）是早期肾功能障碍的一个常见特征，会带来重大风险用于终末期肾病的发展。该提案旨在了解其机制 Dent 病是一种进行性遗传性疾病，其特征是管状蛋白尿，由 2Cl-/H+ 交换剂 ClC-5 突变引起。增强巨蛋白的降解，与过滤蛋白结合的多配体共受体被认为是肾小管蛋白尿的基础然而，马齿病影响的运输步骤尚不清楚，并且 pH 值的影响 vs. Cl- 疾病表型的稳态存在争议。我们将利用基因的组合，形态学、数学建模和生化方法来完成以下任务目标：(1) 确定 ClC-5 敲除 PT 细胞中膜运输受损的步骤； (2) 确定 ClC-5 缺失与巨蛋白表达减少之间的分子机制；和（3）确定在 Dent 小鼠模型中恢复巨蛋白表达和功能的治疗靶点疾病。