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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.

项目总结/摘要本申请为指导临床科学家研究职业发展奖（K 08）正在提交 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：肺泡再生与再生”。我是西北大学的一名肺病和重症监护医生，获得额外的培训，以建立作为研究肺代谢调节的医生科学家的专业知识肺损伤后的发展和修复。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。我目前项目的目标是研究线粒体复合物I在出生后肺发育和流感感染后肺修复中的作用，并鉴定将复合物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，被列为美国十大死亡原因之一。死亡率从30岁到 45%，目前除支持治疗外无有效治疗。一种新的治疗方法是促进肺损伤后的修复。据报道，几种肺上皮细胞亚群对各种损伤作出反应而扩增，并重新繁殖以取代受损的肺泡上皮细胞。知之甚少关于这些上皮干/祖细胞的增殖和分化是如何调节的。我的导师博士 Chandel的实验室先前证明，线粒体呼吸链对呼吸系统的功能至关重要。在一些实施方案中，本发明的组合物用于促进包括角质形成细胞、脂肪细胞和造血干细胞的各种细胞的分化。这些影响是通过活性氧或线粒体代谢物的积累发挥作用的，表观遗传机制，并独立于线粒体的ATP合成功能。是否肺上皮干/祖细胞受线粒体代谢调节的研究尚未进行。我的初步数据提示线粒体复合物I驱动呼吸是肺上皮细胞分化所必需的，干/祖细胞。这些观察结果导致了一个新的假设，即线粒体复合物I驱动呼吸，独立于ATP的产生，是出生后肺发育所必需和充分的，代谢产物（目的1），是必要的流感诱导的成人上皮肺损伤的修复（目的2）。我的项目将提供一个新的机制模型连接线粒体代谢肺上皮细胞干/祖细胞在肺损伤和修复的背景下。该培训计划将促进获得关键的代谢和生化实验室技能，熟练进行动物研究，并解释高来自高维（-omic）平台的通量数据。本提案中计划的活动，包括指导与密切的导师，出席会议，并完成课程的研究- 密集的制度环境，将进一步我继续发展成为一个独立的研究人员。