PODOCYTE ENDOPLASMIC RETICULUM STRESS AND NEPHROTIC SYNDROME

足细胞内质网应激与肾病综合征

基本信息

批准号：
10161772
负责人：
Ying Maggie Chen
金额：
$ 30.5万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161772
关键词：
Ablation Accounting Apoptosis Apoptotic Astrocytes Attenuated Cell Surface Receptors Cessation of life Coupled DNA Sequence Alteration Development Diagnosis End stage renal failure Endoplasmic Reticulum Engineering Functional disorder Genes Genetic Genetic Models Genetic Variation Goals Human Human Genetics Induced Mutation Injury Kidney Kidney Diseases Kidney Failure Knock-out Knockout Mice Laminin Lead Life Link Mediating Missense Mutation Molecular Molecular Target Morbidity - disease rate Mutate Mutation Nephrotic Syndrome Pathogenesis Pathogenicity Pathway interactions Patients Proteins Proteinuria Proto-Oncogene Proteins c-akt Regulation Renal function Research Research Personnel Risk Risk Assessment Role Signal Transduction Signaling Protein Testing Therapeutic Time Transcriptional Regulation Transgenic Mice Translational Research Uncertainty Universities Variant Washington base cohort cost disease phenotype disorder risk effective therapy endoplasmic reticulum stress genetic approach genetic variant glomerular basement membrane high throughput screening in silico in vivo innovation knock-down lamin B2 mortality mouse genetics mouse model mutant neurotrophic factor next generation sequencing novel novel therapeutic intervention novel therapeutics overexpression podocyte response tool transcription factor CHOP treatment strategy variant of unknown significance

项目摘要

Abstract Nephrotic syndrome (NS) is characterized by heavy proteinuria and increased risk of loss of kidney function. It causes serious morbidity and high mortality, accounting for 15% of prevalent end-stage renal disease at an annual cost of more than $3 billion in the US. There is no effective treatment for most cases of NS caused by genetic mutations. Our research has been focused on a monogenic form of NS caused by a missense mutation (C321R) of LAMB2, one of the most commonly mutated genes in NS. Laminin 2 encoded by LAMB2 is a component of laminin-521 ( 5 2 1), the major laminin trimer of the glomerular basement membrane (GBM). Using our established knockout/transgenic mouse model, we have found that podocyte endoplasmic reticulum (ER) stress and subsequent defective secretion of misfolded C321R-LAMB2 from podocytes to the GBM lead to proteinuria. Furthermore, we have recently discovered an ER soluble factor that promotes the survival of ER-stressed podocytes. The overall goals of this proposal are to delineate molecular mechanisms regulating important death and survival pathways activated by the C321R-LAMB2 mutation-induced podocyte ER stress, to determine the contribution of podocyte ER stress in NS patients carrying putative deleterious missense variants, and to investigate novel treatment strategies for genetic forms of NS. To accomplish our research goals, we will utilize mouse genetic models and access two major human NS cohorts, Nephrotic Syndrome Study Network (NEPTUNE) and the Washington University Kidney Translational Research Core (WU KTRC). We have assembled an interdisciplinary team including multiple co-investigators and collaborators with the required expertise in pioneering ER stress research, human and mouse genetics, next generation sequencing, and high throughput screening. The proposed study will help us classify NS patients based on underlying molecular mechanisms, stratify disease risk, and discover highly-targeted treatments for NS patients caused by podocyte ER dysfunction.

抽象的肾病综合征 (NS) 的特点是大量蛋白尿和肾丢失风险增加功能。它导致严重的发病率和高死亡率，占流行的终末期肾病的 15% 美国每年因该疾病造成的损失超过 30 亿美元。大多数病例没有有效的治疗方法 NS是由基因突变引起的。我们的研究重点是由单基因形式的 NS 引起 LAMB2 的错义突变 (C321R)，NS 中最常见的突变基因之一。层粘连蛋白2编码 LAMB2 是层粘连蛋白 521 ( 5 2 1) 的组成部分，层粘连蛋白是肾小球基底的主要层粘连蛋白三聚体膜（GBM）。使用我们建立的敲除/转基因小鼠模型，我们发现足细胞内质网 (ER) 应激和随后错误折叠的 C321R-LAMB2 的分泌缺陷足细胞到达 GBM 会导致蛋白尿。此外，我们最近发现了一种 ER 可溶性因子促进 ER 应激足细胞的存活。该提案的总体目标是描绘调节重要死亡和死亡的分子机制。由 C321R-LAMB2 突变诱导的足细胞 ER 应激激活的生存途径，以确定足细胞 ER 应激对携带假定的有害错义变异的 NS 患者的贡献，以及研究遗传性 NS 的新治疗策略。为了实现我们的研究目标，我们将利用小鼠遗传模型并访问两个主要的人类 NS 队列，肾病综合征研究网络（NEPTUNE）和华盛顿大学肾脏转化研究核心（WU KTRC）。我们有组建了一个跨学科团队，包括多名共同研究者和合作者，并具有所需的能力在开创性 ER 应激研究、人类和小鼠遗传学、下一代测序和高通量筛选。拟议的研究将帮助我们根据潜在的分子机制对 NS 患者进行分类，分层疾病风险，并发现针对足细胞 ER 功能障碍引起的 NS 患者的高针对性治疗方法。