The role of Alveolar Epithelial Cell Metabolic Reprogramming in Idiopathic Pulmonary Fibrosis

摘要 特发性肺纤维化（IPF）是一种以功能障碍性创伤为特征的不明原因的致死性肺部疾病 肺部愈合和异常纤维化重塑夺去了超过40，000名美国人的生命 年IPF的中位年龄为66岁，患者的平均预期寿命为3年。的 对这种疾病的科学发现一直很缓慢，只有两种FDA批准的药物 不能逆转或治愈疾病的药物。鉴于美国人口的寿命越来越长， 了解这种疾病的潜在驱动因素至关重要。最近，上皮生物学的关键作用 这种疾病的发展和进展已经成为一个高影响力的问题，需要进一步研究。 澄清。为了解决这一未满足的需求，我们将利用一种新的IPF临床前小鼠模型（SftpcI 73 T）， 密切概括了人类疾病的许多方面，并允许亚临床事件的时间建模 在其发病机制中。基于令人信服的初步数据，该项目的总体目标是利用 上述新的Sftpc模型，以表征上皮细胞中的代谢功能障碍并鉴定 药物干预的潜在途径。在这个模型中，我发现肺泡II型 上皮细胞（AT 2）经历代谢的显著变化，包括向增强的糖酵解转变， TCA循环中间体的改变和线粒体动力学的变化。由此我推测， 在IPF中，AT 2细胞质量控制的获得性缺陷启动了IPF中代谢重编程的级联反应， 促进促纤维化AT 2内表型的细胞，其可以启动、放大和增强纤维形成。 我们将在两个具体目标中检验这一假设：1）使用SftpcI 73 T突变体，表征AT 2的范围， IPF中的代谢重编程，重点关注线粒体功能、线粒体动力学和TCA 中间通量2)确定代谢改变对AT 2功能在纤维化过程中的影响， 体外和体内。这项研究的结果将描述上皮细胞代谢重编程的作用， 功能障碍和阐明治疗干预的潜在靶点。在IPF范围之外，上皮 功能障碍是慢性和急性肺部疾病的一个重要方面，特别是在COVID-19的情况下 流行病

Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown cause marked by dysfunctional wound healing and aberrant fibrotic remodeling of the lung that claims the lives of more than 40,000 Americans each year. The median age of IPF is 66 years and patients have an average life expectancy of 3 years. The scientific discovery into this disease has been slow and has resulted in only two FDA approved medications that do not reverse or cure the disease. In light of the increasing longevity of the American population, understanding the underlying drivers of this disease is essential. Recently, the critical role of epithelial biology in the development and progression of this disease has become a high impact question that requires further elucidation. To address this unmet need, we will utilize a novel preclinical murine model (SftpcI73T) of IPF that closely recapitulates many aspects of the human disease and permits temporal modeling of subclinical events in its pathogenesis. Founded in compelling preliminary data, the overall goal of this project is to capitalize on the aforementioned novel Sftpc model to characterize the metabolic dysfunction in epithelial cells and identify potential pathways for pharmacologic intervention. In this model, I have found that the alveolar type II epithelial cell (AT2) undergoes marked changes in metabolism including a shift towards enhanced glycolysis, alterations in TCA cycle intermediates, and changes in mitochondrial dynamics. From this I hypothesize that in IPF an acquired deficiency in AT2 cell quality control initiates a cascade of metabolic reprogramming in the cell that promotes a profibrotic AT2 endophenotype(s) which can initiate, amplify and enhance fibrogenesis. We will test this hypothesis in two specific aims: 1) Using the SftpcI73T mutant, characterize the scope of AT2 metabolic reprogramming in IPF focusing on mitochondrial function, mitochondrial dynamics, and TCA intermediate flux. 2) Determine the effect of altered metabolism on AT2 function during fibrogenesis both in- vitro and in-vivo. The findings from this study will characterize the role of metabolic reprogramming in epithelial dysfunction and elucidate potential targets for therapeutic intervention. Beyond the scope of IPF, epithelial dysfunction is an important aspect of chronic and acute lung disease, particularly in light of the COVID-19 pandemic.