Mitochondrial metabolic regulation of lung epithelium: alveolar generation and regeneration

肺上皮的线粒体代谢调节：肺泡的生成和再生

• 批准号: 10241362
• 负责人: Seunghye Han
• 金额: $ 16.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241362
• 关键词: ATP Synthesis Pathway; Address; Adipocytes; Adult; Adult Respiratory Distress Syndrome; Affect; Alveolar; Anabolism; Animals; Biochemical; Biological; Biological Markers; Birth; Blood; Cause of Death; Cell Aging; Cell Death; Cell Differentiation process; Cell Proliferation; Cells; Cessation of life; Clinical; Complex; Critical Care; Data; Defect; Development; Disease; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Failure; Functional disorder; Future; Generations; Genetic; Genomic DNA; Goals; Hematopoietic stem cells; Hypoxemia; In Vitro; Infection; Influenza; Influenza A virus; Injury; Intrinsic factor; K-Series Research Career Programs; Laboratories; Lead; Life; Link; Lung; Mentors; Mentorship; Metabolic; Methylation; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Molecular Genetics; Natural regeneration; Organelles; Organoids; Oxygen; Pathway interactions; Patients; Pharmacology; Phenotype; Physicians; Play; Pneumonia; Process; Production; Proteins; Proton Pump; Reactive Oxygen Species; Regulation; Reporting; Research; Research Personnel; Respiration; Respiratory Chain; Respiratory Failure; Role; Scientist; Sepsis; Signal Transduction; Stem cell pluripotency; Structure; Structure of parenchyma of lung; Supportive care; System; Techniques; Testing; Training; United States; Universities; Work; adipocyte differentiation; alveolar epithelium; base; career; cell type; effective therapy; epithelial injury; epithelial stem cell; influenza infection; injury and repair; insight; keratinocyte; keratinocyte differentiation; loss of function; lung development; lung injury; lung regeneration; lung repair; macromolecule; metabolic abnormality assessment; metabolomics; mitochondrial dysfunction; mitochondrial metabolism; mortality; multidimensional data; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; postnatal; prevent; repaired; reparative process; response; skills; stem; stem cells; symposium; therapeutic target; tool; transcriptome sequencing; yeast protein

Project Summary/Abstract This application for a Mentored Clinical Scientist Research Career Development Award (K08) is being submitted by SeungHye Han, MD, MPH, and entitled “Mitochondrial metabolic regulation of lung epithelium: alveolar generation and regeneration.” I am a pulmonary and critical care physician at Northwestern University who is obtaining additional training to build expertise as a physician scientist studying metabolic regulation of lung development and repair after lung injury. My long-term research goal is to find new therapeutic targets to promote lung repair in patients with acute respiratory distress syndrome (ARDS). The objective of my current project is to study the role of mitochondrial complex I on postnatal lung development and lung repair after influenza infection, and identify metabolites and pathways that link complex I driven respiration to lung stem/progenitor cells. ARDS is a devastating disorder commonly associated with pneumonia and influenza infection, which are categorized as one of the ten leading causes of death in the United States. The mortality rate is high from 30 to 45%, and there is no current effective therapy except supportive care. One novel therapeutic approach is to promote lung repair after injury has occurred. Several lung epithelial subpopulations have been reported to expand in response to various insults, and repopulate to replace damaged alveolar epithelial cells. Little is known about how proliferation and differentiation are regulated in these epithelial stem/progenitor cells. My mentor Dr. Chandel’s laboratory previously demonstrated that the mitochondrial respiratory chain is essential for the differentiation of various cells including keratinocytes, adipocytes, and hematopoietic stem cells. These effects are exerted through reactive oxygen species or the accumulation of mitochondrial metabolites that control epigenetic machinery, and are independent of the ATP synthetic function of mitochondria. Whether lung epithelial stem/progenitor cells are regulated by mitochondrial metabolism has not been studied. My preliminary data suggest that mitochondrial complex I driven respiration is required for the differentiation of lung epithelial stem/progenitor cells. These observations led to the novel hypothesis that mitochondrial complex I driven respiration, independent of ATP generation, is necessary and sufficient for postnatal lung development via metabolites (Aim 1), and is necessary for the repair of influenza-induced adult epithelial lung injury (Aim 2). My project will provide a new mechanistic model linking mitochondrial metabolism to lung epithelial stem/progenitor cells in the context of lung injury and repair. The training plan will promote acquisition of key metabolic and biochemical laboratory skills, proficiency with conducting animal studies, and interpretation of high throughput data from high dimensional (-omic) platforms. The activities planned in this proposal, including guidance with close mentorship, attendance of conferences, and completion of coursework in a research- intensive institutional environment, will further my continued development into an independent researcher.

项目概要/摘要 正在提交指导临床科学家研究职业发展奖（K08）的申请 作者：SeungHye Han，医学博士、公共卫生硕士，题为“肺上皮细胞的线粒体代谢调节：肺泡 的产生和再生。”我是西北大学的一名肺部和重症监护医生， 获得额外的培训，以积累作为研究肺代谢调节的医师科学家的专业知识 肺损伤后的发育和修复。我的长期研究目标是寻找新的治疗靶点来促进 急性呼吸窘迫综合征（ARDS）患者的肺修复。我当前项目的目标是 研究线粒体复合物 I 对产后肺发育和流感感染后肺修复的作用， 并确定将复合物 I 驱动的呼吸与肺干/祖细胞联系起来的代谢物和途径。 ARDS 是一种破坏性疾病，通常与肺炎和流感感染相关， 被列为美国十大死因之一。 30岁以上死亡率很高 45%，目前除了支持治疗外没有有效的治疗方法。一种新颖的治疗方法是 促进损伤后的肺部修复。据报道，几种肺上皮亚群 响应各种损伤而扩张，并重新填充以替换受损的肺泡上皮细胞。鲜为人知 关于如何调节这些上皮干/祖细胞的增殖和分化。我的导师博士。 钱德尔的实验室此前证明线粒体呼吸链对于 各种细胞的分化，包括角质形成细胞、脂肪细胞和造血干细胞。这些影响 通过活性氧或控制线粒体代谢物的积累来发挥作用 表观遗传机制，并且独立于线粒体的 ATP 合成功能。是否为肺上皮型 干/祖细胞受线粒体代谢调节尚未研究。我的初步数据 表明线粒体复合物 I 驱动的呼吸对于肺上皮细胞的分化是必需的 干/祖细胞。这些观察结果得出了线粒体复合物 I 驱动的新假设 呼吸独立于 ATP 的产生，对于出生后肺部发育来说是必要且充分的 代谢物（目标 1），并且对于修复流感引起的成人上皮性肺损伤（目标 2）是必需的。 我的项目将提供一种将线粒体代谢与肺上皮联系起来的新机制模型 肺损伤和修复中的干/祖细胞。培训计划将促进关键人才的获取 代谢和生化实验室技能、进行动物研究的熟练程度以及高水平的解释 来自高维（-omic）平台的吞吐量数据。本提案中计划的活动包括 密切指导、参加会议以及完成研究课程的指导 密集的制度环境，将进一步我继续发展成为一名独立研究员。