The Role of Autophagy in the Pathogenesis of interstitial Lung Disease

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“磨损”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，导致细胞碎片的积累、损伤和细胞衰老或死亡。该观察结果导致本申请的中心假设，即自噬功能障碍促成间质性肺病（ILD）典型的迟发性和/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，进而促进异常纤维化修复。表面活性蛋白C（SP-C）是研究自噬在ILD中作用的一个非常容易处理的模型：肺中SP-C的表达仅限于II型上皮细胞，编码SP-C（SFTPC）的基因突变与散发性和遗传性ILD相关。在本申请中，我们提出了初步的发现，即特异性SFTPC突变仅通过自噬降解，以及在ILD发病机制中涉及自噬的其他新数据。提出了三个具体目标来研究转染细胞、新型转基因小鼠模型和人类ILD患者肺组织中的SFTPC突变，目的是鉴定靶向突变型SP-C进行自噬的分子途径以及该途径在ILD发病机制中的作用。具体目标1将检验以下假设：易聚集的突变SP-C蛋白通过自噬选择性降解，并且抑制该途径导致细胞毒性SP-C的积累。具体目标2将测试的假设，一个新的质量控制途径在内质网介导的快速识别和交付SP-C的自噬途径。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，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、新的治疗靶点和适当的动物模型，以促进ILD发病途径的识别和新型治疗模式的开发。

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.