Metabolic reprogramming of Alveolar Type 2 cells in response to lung injury

项目总结 越来越多的证据表明，肺泡上皮细胞和成纤维细胞的线粒体功能受损 会扰乱肺部修复。线粒体生物能量学和新陈代谢在茎和祖细胞中起着核心作用 细胞在其他器官中的功能，在线粒体呼吸和糖酵解之间转换，以满足 修复，但在肺部受到的关注有限。这项提案将使用一种罕见的肺部疾病作为模型 研究生物能量学和新陈代谢如何调节肺泡上皮修复的动态事件。 HPS1基因突变的1型Hermansky Pudlak综合征(HPS-1)患者表现出高度渗透性，早期 起病，纤维化的间质性肺病。我们假设，通过扰乱线粒体网络， HPS1的丢失损害了线粒体的呼吸，促进了驱动AT2的代谢重新编程 以牺牲分化为代价的祖细胞增殖，并刺激促纤维化的上皮细胞向- 成纤维细胞信号。目标1将确定HPS1在肺泡2型(AT2)细胞生物能量学和 新陈代谢，目标2将确定HPS1缺失对肺泡上皮修复的影响，目标3将确定 AT2细胞中的新陈代谢重新编程如何驱动纤维化修复。我们将使用Robust来完成这些研究 MLE15细胞模型，白耳小鼠原代肺细胞Hps1的全局失活，一种新的Hps1/Flox 小鼠检测AT2细胞和成纤维细胞在HPS1丢失背景下对修复的选择性贡献， 具有常见HPS1突变的患者来源的iPS细胞提供与人类的翻译相关性，以及 重复的博莱霉素模型来概括我们的发现，超越了一种罕见的肺部疾病。我们的专业知识 实验室小组与范德比尔特的肺和线粒体群落的力量相结合 独一无二的定位，使我们能够成功地进行这些实验。我们期望拟议的研究将确定 HPS1在HPS 1型肺部疾病中的作用，将生物能量学和新陈代谢机械地整合到 肺泡修复，并为越来越多的纤维化间质中AT2细胞的生物能量衰竭提供洞察力 肺部疾病。

PROJECT SUMMARY Growing evidence indicates that disrupted mitochondrial function in alveolar epithelial cells and in fibroblasts can disrupt lung repair. Mitochondrial bioenergetics and metabolism play central roles in stem and progenitor cell functions in other organs, shifting between mitochondrial respiration and glycolysis to meet the needs of repair, but have received limited attention in the lung. This proposal will use a rare lung disease as model to investigate how bioenergetics and metabolism regulate the dynamic events of alveolar epithelial repair. Hermansky Pudlak syndrome type 1 (HPS-1) patients with mutations in HPS1 exhibit highly penetrant, early onset, fibrosing interstitial lung disease. We hypothesize that by disrupting mitochondrial networking, loss of HPS1 impairs mitochondrial respiration, fostering metabolic reprogramming that drives AT2 progenitor cell proliferation at the expense of differentiation, and stimulates pro-fibrotic epithelial-to- fibroblast signaling. Aim 1 will establish the role of HPS1 in alveolar type 2 (AT2) cell bioenergetics and metabolism, Aim 2 will determine the impact of HPS1 loss on alveolar epithelial repair, and Aim 3 will identify how metabolic reprograming in AT2 cells drives fibrotic repair. We will accomplish these studies using robust MLE15 cell models, primary lung cells from pale ear mice with global inactivation of Hps1, a novel Hps1flox/flox mouse to examine selective contributions of AT2 cells and fibroblasts to repair in the setting of HPS1 loss, patient-derived iPS cells with the common HPS1 mutation to provide translational relevance to humans, and the repetitive bleomycin model to generalize our findings beyond a rare lung disease. The expertise of our laboratory group coupled with the strength of the pulmonary and mitochondrial communities at Vanderbilt uniquely position us to successfully execute these experiments. We expect that proposed studies will establish a role for HPS1 in HPS type 1 lung disease, integrate bioenergetics and metabolism mechanistically into alveolar repair, and provide insight into AT2 cell bioenergetic failure in a growing number of fibrosing interstitial lung diseases.