The Role of Autophagy in the Pathogenesis of interstitial Lung Disease

自噬在间质性肺疾病发病机制中的作用

基本信息

批准号：
8502747
负责人：
Timothy Edward Weaver
金额：
$ 48.38万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502747
关键词：
Acute Address Age Alleles Alveolar Animal Model Autophagocytosis Biological Markers Cell Aging Cell Death Cells Cellular Structures Chronic Complex Data Defect Detection Development Diagnosis Disease Disease Progression Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway Epithelial Cells Excision Figs - dietary Functional disorder Gene Expression Genes Genetic Genotype Goals Hamman-Rich syndrome Homeostasis Human Individual Injury Interstitial Lung Diseases Knock-in Mouse Knowledge Link Lung Lung diseases Lysosomes Maintenance Mass Spectrum Analysis Mean Survival Times Mediating Modeling Molecular Molecular Chaperones Molecular Profiling Mus Mutation Natural History Organelles Pathogenesis Pathway interactions Patients Process Proteins Pulmonary Surfactant-Associated Protein C Quality Control Risk Role Structure Structure of parenchyma of lung Testing Transgenic Mice Type II Epithelial Receptor Cell Ubiquitin cell injury citrate carrier cytotoxic effective therapy inhibition of autophagy mouse model multicatalytic endopeptidase complex mutant new therapeutic target novel novel diagnostics overexpression protein aggregate repaired research study therapeutic target tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Maintenance of cellular homeostasis requires synthesis of new proteins and organelles and efficient removal of "worn out" cell components. Degradation processes are carried via two mechanisms, the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. Defects in both of these catabolic pathways have been linked to pathogenesis of a variety of diseases. Autophagic function declines with age leading to accumulation of cellular debris, injury and cell senescence or death. This observation leads to the central hypothesis of this application, that autophagic dysfunction contributes to the late onset and/or acute exacerbations typical of interstitial lung disease (ILD). We postulate that autophagic dysfunction in alveolar epithelial cells leads to chronic epithelial cell injury that, in turn, promotes aberrant fibrotic repair. Surfactant protein C (SP-C) represents a highly tractable model to study the role of autophagy in ILD: SP-C expression in the lung is limited to the type II epithelial cell and mutations in the gene encoding SP-C (SFTPC) are associated with sporadic and heritable ILD. In this application, we present preliminary findings that specific SFTPC mutations are degraded exclusively by autophagy and additional new data implicating autophagy in the pathogenesis of ILD. Three specific aims are proposed to study SFTPC mutations in transfected cells, novel transgenic mouse models and lung tissue from human ILD patients, with the goal of identifying the molecular pathway(s) that targets mutant SP-C to autophagy and the role of this pathway in the pathogenesis of ILD. Specific Aim 1 will test the hypothesis that aggregation-prone, mutant SP-C proteins are selectively degraded by autophagy and that inhibition of this pathway leads to accumulation of cytotoxic SP-C. Specific Aim 2 will test the hypothesis that a novel quality control pathway in the endoplasmic reticulum mediates rapid identification and delivery of SP-C to the autophagic pathway. Specific Aim 3 will test the hypothesis that autophagic dysfunction in novel transgenic mouse models leads to epithelial cell injury that, in turn, promotes the onset and/or exacerbation of ILD. These studies will provide new diagnostic tools, new therapeutic targets and appropriate animal models to facilitate identification of pathogenetic pathways and development of novel treatment paradigms for ILD.

描述（由申请人提供）：维持细胞稳态需要合成新的蛋白质和细胞器，并有效去除“破旧”细胞成分。降解过程是通过两种机制（泛素 - 蛋白酶体途径和自噬 - 赖氨体途径）进行的。这两种分解代谢途径的缺陷都与多种疾病的发病机理有关。自噬功能随着年龄的增长而下降，导致细胞碎片，损伤和细胞衰老或死亡的积累。这一观察结果导致了该应用的中心假设，即自噬功能障碍有助于典型的间隙肺病（ILD）的晚期发作和/或急性加重。我们假设肺泡上皮细胞中的自噬功能障碍会导致慢性上皮细胞损伤，从而促进异常的纤维化修复。表面活性剂蛋白C（SP-C）代表了一个高度易于处理的模型，用于研究自噬在ILD中的作用：SP-C在肺中的表达仅限于II型上皮细胞，并且编码SP-C（SFTPC）基因中的突变与散发性和可遗传的ILD有关。在此应用程序中，我们提出了初步发现，即特定的SFTPC突变仅由自噬和其他新数据降解，这些数据与ILD的发病机理有关。提出了三个具体目的，以研究人ILD患者的转染细胞，新型的转基因小鼠模型和肺组织中的SFTPC突变，目的是鉴定靶向突变体SP-C的分子途径，该途径将突变体SP-C靶向自噬以及该途径在ILD病原体中的作用。具体的目标1将检验以下假设：易于自动噬菌体，易于选择性地降解聚集的突变体SP-C蛋白，并且该途径的抑制会导致细胞毒性SP-C的积累。具体目标2将检验以下假设：内质网中新型质量控制途径可介导SP-C的快速鉴定和递送到自噬途径。具体目标3将检验以下假设：新型转基因小鼠模型中的自噬功能障碍会导致上皮细胞损伤，从而促进了ILD的发作和/或加剧。这些研究将提供新的诊断工具，新的治疗靶标和适当的动物模型，以促进致病途径的鉴定和ILD新型治疗范式的发展。