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

基本信息

批准号：
10681479
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
项目类别：
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/10681479
关键词：
ATP Synthesis Pathway Acute Respiratory Distress Syndrome Address Adipocytes Adult Affect Alveolar Anabolism Animals Biochemical Biological Biological Markers Birth Blood Categories Cause of Death Cell Aging Cell Death Cell Proliferation Cells Cessation of life Clinical Complex Cre lox recombination system Critical Care Data Defect Development Disease Environment Epigenetic Process Epithelial Cells Epithelium Failure Functional disorder Future Generations Genetic Genomic DNA Goals Hematopoietic stem cells Hypoxemic Respiratory Failure In Vitro Infection Influenza Influenza A virus Injury Institution Intrinsic factor K-Series Research Career Programs Laboratories Lead Life Link Lung Mentors Mentorship Metabolic Methylation Mitochondria Mitochondrial Electron Transport Complex I Modeling Molecular Natural regeneration Organelles Organoids Oxygen Pathway interactions Patients Phenotype Physicians Pneumonia Process Production Proliferating Proteins Proton Pump Reactive Oxygen Species Regulation Reporting Research Research Personnel Respiration Respiratory Chain Role Scientist 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 candidate identification career cell type effective therapy epithelial injury epithelial repair epithelial stem cell gain of function inducible Cre influenza infection 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 pharmacologic postnatal prevent repaired reparative process response sepsis induced ARDS skills stem cell differentiation stem cells symposium therapeutic target tool transcriptome sequencing yeast protein

项目摘要

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。