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：
10363709
负责人：
Ora A Weisz
金额：
$ 46.95万
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/10363709
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.

抽象的肾脏因内吞蛋白的内吞吸收受损而导致的肾小管蛋白尿近端小管（PT）是早期肾功能障碍的常见特征，它带来了显着风险用于开发末期肾脏疾病。该建议旨在了解机械凹陷疾病的基础，这是一种以管状蛋白尿为特征的进行性遗传疾病，由2cl-/h+交换器CLC-5中的突变引起。增强Megalin的降解，一个与过滤的蛋白结合的多物体共受体，被认为是肾小管蛋白尿的基础然而，疾病的贩运行为的一步尚不清楚，pH的贡献与疾病表型的Cl-稳态相对于Cl-稳态。我们将利用遗传的组合，形态学，数学建模和生化方法来完成以下目的：（1）确定CLC-5敲低PT细胞中受损的膜流量中的步骤；（2）确定将CLC-5损失与降低梅加林表达联系起来的分子机制；（3）确定用于恢复巨蛋白表达和功能在凹痕模型中的梅加林表达和功能的治疗靶标疾病。