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.

项目摘要/摘要 这项申请指导的临床科学家研究职业发展奖（K08）正在提交 由MD，MPH的Seunghye Han和标题为“肺上皮的线粒体代谢调节：牙槽 一代和再生。“我是西北大学的肺和重症监护身体 获得额外的培训以建立专业知识作为研究肺代谢调节的物理科学家 肺部受伤后发育和修复。我的长期研究目标是找到新的治疗靶标以促进 急性呼吸窘迫综合征（ARDS）患者的肺修复。我当前项目的目的是 研究线粒体复合物I对影响力感染后产后肺发育和肺修复的作用， 并确定将复合物I驱动呼吸与肺茎/祖细胞联系起来的代谢产物和途径。 ARDS是一种毁灭性疾病，通常与肺炎和影响力感染有关， 被归类为美国十个主要死亡原因之一。死亡率从30到30 45％，除支持护理外，目前没有有效的治疗。一种新颖的治疗方法是 受伤后促进肺修复。据报道几个肺上皮亚群 响应各种侮辱，并重新填充以替代受损的肺泡上皮细胞。鲜为人知 关于在这些上皮茎/祖细胞中如何调节增殖和分化。我的导师博士 钱德尔的实验室先前证明，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 通过活性氧或控制的线粒体代谢产物的积累来施加 表观遗传机制，与线粒体的ATP合成功能无关。是否肺上皮 茎/祖细胞受线粒体代谢调节，尚未研究。我的初步数据 建议线粒体复合物I驱动呼吸是肺上皮分化需要的 茎/祖细胞。这些观察结果导致了新的假设，即线粒体复合物I驱动 独立于ATP生成的呼吸是通过 代谢物（AIM 1），对于修复受影响的成年上皮肺损伤是必不可少的（AIM 2）。 我的项目将提供一个新的机械模型，将线粒体代谢与肺上皮联系起来 在肺损伤和修复的背景下，茎/祖细胞。培训计划将促进收购关键 代谢和生化实验室技能，熟练进行动物研究以及对高的解释 来自高维（-omic）平台的吞吐量数据。在本提案中计划的活动，包括 在研究中以紧密的心态，会议的出席以及完成课程的指导 - 密集的机构环境将使我继续发展成为一名独立研究人员。