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

项目摘要 越来越多的证据表明，在肺泡上皮细胞和成纤维细胞中， 会破坏肺的修复线粒体生物能量学和代谢在干细胞和祖细胞中起着重要作用 其他器官中的细胞功能，在线粒体呼吸和糖酵解之间转换，以满足 修复，但在肺中受到的关注有限。这项提案将使用一种罕见的肺部疾病作为模型， 研究生物能量学和代谢如何调节肺泡上皮修复的动态事件。 HPS 1突变的Hermansky Pudlak综合征1型（HPS-1）患者表现出高度渗透性，早期 纤维化间质性肺病我们假设通过破坏线粒体网络， HPS 1的缺失损害线粒体呼吸，促进代谢重编程，驱动AT 2 以分化为代价的祖细胞增殖，并刺激促纤维化上皮细胞向 成纤维细胞信号传导目的1将确定HPS 1在肺泡2型（AT 2）细胞生物能量学中的作用， 目标2将确定HPS 1缺失对肺泡上皮修复的影响，目标3将确定HPS 1缺失对肺泡上皮修复的影响， AT 2细胞中的代谢重编程如何驱动纤维化修复。我们将使用强大的 MLE 15细胞模型，来自Hps 1整体失活的白耳小鼠的原代肺细胞，一种新的Hps 1flox/flox 小鼠以检查AT 2细胞和成纤维细胞在HPS 1丧失的情况下对修复的选择性贡献， 具有常见HPS 1突变的患者来源的iPS细胞，以提供与人类的翻译相关性，以及 重复的博来霉素模型来概括我们的发现，而不仅仅是一种罕见的肺部疾病。的专业知识 再加上范德比尔特的肺和线粒体群落的强度 使我们能够成功地进行这些实验。我们预计，拟议的研究将建立 HPS 1在HPS 1型肺疾病中的作用，将生物能量学和代谢机制整合到 肺泡修复，并提供洞察AT 2细胞生物能量衰竭，在越来越多的纤维化间质 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.