Surfactant protein C mutations and interstitial lung diease

描述(由申请人提供)： 表面活性蛋白C(SP-C)是一种由35个氨基酸组成的肺特异性疏水肽，可增强表面活性磷脂的生物物理活性。SP-C基因20多个不同突变的杂合表达与慢性间质性肺疾病(ILD)有关，以及易于聚集的ProSP-C COOH末端与与家族性阿尔茨海默样痴呆(称为Brichos)相关的蛋白质之间的结构同源性的证明，突显了SP-C对肺部健康和疾病的重要性。该项目的总体目标是进一步了解Brichos突变SP-C表达作为间质性肺疾病相关上皮功能障碍的病因和模型的潜在后果的分子机制。我们假设，SP-C基因的突变导致异常蛋白产物的发展，这些蛋白产物采用非天然构象，导致聚集和产生有毒的功能获得。肺泡上皮细胞(AEC)最初通过激活旨在纠正错误折叠的未折叠蛋白反应(UPR)来响应易于聚集的SP-C Brichos蛋白。UPR不能实现重折叠会导致细胞处理程序的激活，包括内质网相关降解(ERAD)和宏自噬以增加突变蛋白的清除。面对失败的处置，延长的UPR激活(即内质网应激)导致危险信号的产生，从而影响细胞因子的合成和细胞凋亡，从而导致ILD的创面异常愈合和纤维化重塑。我们的实验方法利用遗传和药理学技术来剖析与ILD相关的SP-C基因折叠突变的潜在细胞反应的分子途径。我们实验室开发的突变SP-C表达的体外细胞模型将与旨在干预蛋白稳态通路的工具和试剂相结合，例如UPR[特异性目标1]以及ERAD和自噬[特异性目标2]，这些途径参与AEC用来处理异常蛋白客户的稳态反应。此外，这些模型系统将被用来评估新出现的治疗策略，这些治疗策略被证明对其他蛋白增生性疾病有效[特定目标3]，从而为这种毁灭性的肺部疾病的治疗提供了从长凳到床边的快速转换的可能性。

DESCRIPTION (provided by applicant): Surfactant protein C (SP-C) is a 35 amino acid lung-specific hydrophobic peptide that enhances the biophysical activity of surfactant phospholipid. The importance of SP-C to lung health and disease has been underscored by the observations that heterozygous expression of over 20 different mutations in the SP-C gene in humans is associated with chronic interstitial lung disease (ILD) and by the demonstration of structural homology between the aggregation-prone proSP-C COOH terminus and a protein associated with familial Alzheimer-like dementia (termed BRICHOS). The overall goal of this project is to further understand the molecular mechanisms underlying the consequences of BRICHOS mutant SP-C expression as both an etiology for and a model of the epithelial dysfunction associated with the pathophysiology of interstitial lung disease. We hypothesize that mutations in the SP-C gene induce the development of aberrant protein products that adopt non-native conformations that lead to aggregation and production of a toxic gain of function. Alveolar epithelial cells (AEC) initially respond to aggregation-prone SP-C BRICHOS protein by activating the unfolded protein response (UPR) aimed at correcting misfolding. Failure of the UPR to effect refolding results in activation of cellular disposal programs including ER- Associated Degradation (ERAD) and macroautophagy to augment mutant protein clearance. In the face of failed disposal, prolonged UPR activation (i.e. "ER Stress") results in elaboration of danger signals to effect cytokine elaboration and apoptosis which contribute to the abnormal wound healing and fibrotic remodeling seen in ILD. Our experimental approach utilizes genetic and pharmacologic techniques to dissect out molecular pathways underlying the cellular response to folding mutations in the SP-C gene associated with ILD. In vitro cellular models of mutant SP-C expresson developed in our laboratory will be combined with tools and reagents designed to interogate proteostatic pathways such as the UPR [Specific Aim 1] as well as ERAD and autophagy [Specific Aim 2] that participate in the homeostatic response used by AEC to handle abnormal protein clients. In addition, these model systems will be used to evaluate emerging therapeutic strategies shown to be effective in other proteostatic diseases [Specific Aim 3] thus offering the possibilty of rapid bench to bedside translation for the treatment of this devastating lung disease.