The Role of Autophagy in the Pathogenesis of interstitial Lung Disease

描述(申请人提供)：维持细胞内稳态需要合成新的蛋白质和细胞器，并有效地去除“破旧”的细胞成分。降解过程通过两种机制进行，泛素-蛋白酶体途径和自噬-溶酶体途径。这两种分解代谢途径的缺陷都与多种疾病的发病机制有关。自噬功能随着年龄的增长而下降，导致细胞碎片堆积、损伤和细胞衰老或死亡。这一观察结果导致了这一应用的中心假设，即自噬功能障碍导致间质性肺疾病(ILD)典型的晚发和/或急性加重。我们推测肺泡上皮细胞自噬功能障碍导致慢性上皮细胞损伤，进而促进异常纤维修复。肺表面活性蛋白C(SP-C)是研究自噬在ILD中作用的一种高度简便的模型：SP-C在肺中的表达仅限于II型上皮细胞，SP-C编码基因(SFTPC)的突变与散发性和遗传性ILD有关。在这个应用中，我们提出了初步的发现，特定的SFTPC突变是通过自噬和其他新的数据来降解的，自噬与ILD的发病机制有关。我们提出了三个特定的目标来研究转基因细胞、新型转基因小鼠模型和人类ILD患者肺组织中的SFTPC突变，目的是确定针对突变的SP-C到自噬的分子途径(S)，以及该途径在ILD发病机制中的作用。特定目标1将检验这样的假设，即易于聚集的突变的SP-C蛋白通过自噬选择性地降解，并且抑制这一途径会导致细胞毒性SP-C的积累。特定目的2将验证这样的假设，即内质网中的一种新的质量控制途径介导了SP-C的快速识别和向自噬途径的递送。特殊目的3将验证这样一种假设，即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，进而促进ILD的发生和/或恶化。这些研究将提供新的诊断工具、新的治疗靶点和合适的动物模型，以便于识别ILD的发病途径和开发新的治疗范例。

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.