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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

基本信息

批准号：
10446870
负责人：
Susan H. Guttentag
金额：
$ 60.86万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/10446870
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 Epithelial Cells 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 Lung Lung diseases Maintenance Metabolic Metabolism Methods Mitochondria Modeling Mus Mutation Myofibroblast Newly Diagnosed Organ Pathogenesis Pathway interactions Patients Phenotype Play Positioning Attribute Production Pulmonary Fibrosis Regulation Respiration Role Signal Transduction Structure Support Groups Testing Validation Work alveolar epithelium 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 stem cell function stem cell proliferation stem cells

项目摘要

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.

项目总结