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

肺泡 2 型细胞响应肺损伤的代谢重编程

• 批准号: 10657569
• 负责人: Susan H. Guttentag
• 金额: $ 62.58万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657569
• 关键词: Acute; Age; Alveolar; Attention; Back; Bioenergetics; Bleomycin; Bypass; Cell Differentiation process; Cell model; Cells; Cellular Metabolic Process; Chronic; Coculture Techniques; Communities; Coupled; Data Set; Disease model; Distal; Dose; Ear; Epithelial Cells; Epithelium; Event; Exhibits; Failure; Fibroblasts; Fibrosis; Fostering; Functional disorder; Genes; Genetic Transcription; Glycolysis; Guanosine Triphosphate Phosphohydrolases; Healthcare; Hermanski-Pudlak Syndrome; Human; Impairment; In Vitro; Individual; Injury; Laboratories; LoxP-flanked allele; Lung; Lung diseases; Maintenance; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Mus; Mutation; Myofibroblast; Newly Diagnosed; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Positioning Attribute; Production; Proliferating; Pulmonary Fibrosis; Regulation; Respiration; Role; Signal Transduction; Structure; Support Groups; Testing; Validation; Work; alveolar epithelium; care burden; cell injury; early onset; epithelial injury; epithelial repair; experimental study; fibrotic interstitial lung disease; healing; induced pluripotent stem cell; insight; lung injury; lung repair; mouse model; novel; postnatal development; repaired; response; single-cell RNA sequencing; statistics; stem; stem cell function; stem cell proliferation; stem cells

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.

项目概要 越来越多的证据表明，肺泡上皮细胞和成纤维细胞中的线粒体功能受到破坏 会破坏肺部修复。线粒体生物能学和代谢在干细胞和祖细胞中发挥核心作用 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，但在肺部受到的关注有限。该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。 具有 HPS1 突变的 Hermansky Pudlak 综合征 1 型 (HPS-1) 患者表现出高渗透性、早期 发病，纤维化间质性肺疾病。我们假设通过破坏线粒体网络， HPS1 的缺失会损害线粒体呼吸，促进驱动 AT2 的代谢重编程 祖细胞增殖以牺牲分化为代价，并刺激促纤维化上皮细胞 成纤维细胞信号传导。目标 1 将确定 HPS1 在肺泡 2 型 (AT2) 细胞生物能学中的作用以及 代谢，目标 2 将确定 HPS1 丢失对肺泡上皮修复的影响，目标 3 将确定 AT2 细胞中的代谢重编程如何驱动纤维化修复。我们将使用稳健的方法来完成这些研究 MLE15 细胞模型，来自 Hps1 整体失活的苍耳小鼠的原代肺细胞，一种新型 Hps1flox/flox 小鼠检查 AT2 细胞和成纤维细胞在 HPS1 丢失的情况下对修复的选择性贡献， 源自患者的 iPS 细胞具有常见的 HPS1 突变，可为人类提供翻译相关性，以及 重复博来霉素模型将我们的发现推广到罕见肺部疾病之外。我们的专业知识 实验室小组与范德比尔特大学肺和线粒体群落的实力相结合 使我们能够成功地进行这些实验。我们期望拟议的研究将建立 HPS1 在 HPS 1 型肺部疾病中的作用，将生物能量学和代谢机制整合到 肺泡修复，并深入了解越来越多的纤维化间质中 AT2 细胞生物能衰竭 肺部疾病。