Mitochondrial metabolic regulation of lung epithelium: alveolar generation and regeneration

项目摘要/摘要 正在提交临床科学家导师研究职业发展奖(K08)的申请 作者：SeungHye han，医学博士，公共卫生硕士，题为《肺上皮线粒体代谢调节：肺泡 生生不息。“我是西北大学的肺部和重症监护内科医生 作为研究肺代谢调节的内科科学家，获得额外的培训以积累专业知识 肺损伤后的发育和修复。我的长期研究目标是找到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 研究线粒体复合体I在流感感染后肺发育和肺修复中的作用 并确定将复合体I驱动的呼吸与肺干细胞/祖细胞联系起来的代谢物和途径。 ARDS是一种毁灭性的疾病，通常与肺炎和流感感染有关，这两种疾病 被列为美国十大主要死因之一。死亡率从30%到30%都很高。 45%，目前除了支持性护理外，没有有效的治疗方法。一种新的治疗方法是 促进肺损伤发生后的修复。据报道，有几种肺上皮细胞亚群 扩张以应对各种侮辱，并重新填充以取代受损的肺泡上皮细胞。鲜为人知 关于这些上皮性干细胞/祖细胞的增殖和分化是如何调节的。我的导师Dr。 Chandel的实验室之前证明了线粒体呼吸链对 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 是通过活性氧或控制线粒体代谢产物的积累来施加的 表观遗传机制，并独立于线粒体的ATP合成功能。肺上皮细胞是否 干细胞/祖细胞受线粒体代谢调控的研究尚未见报道。我的初步数据 提示线粒体复合体I驱动的呼吸是肺上皮细胞分化所必需的 干细胞/祖细胞。这些观察结果导致了新的假设，即线粒体复合体I驱动 呼吸作用独立于三磷酸腺苷的生成，是出生后肺发育的必要条件和充分性途径。 代谢物(目标1)，是修复流感引起的成人上皮肺损伤所必需的(目标2)。 我的项目将提供一个新的机制模型，将线粒体新陈代谢与肺上皮细胞联系起来 干细胞/祖细胞与肺损伤和修复的关系。培训计划将促进关键技术的获取 新陈代谢和生化实验室技能，精通进行动物研究，并能解释 来自高维(经济)平台的吞吐量数据。本提案中计划的活动，包括 通过密切指导、出席会议和完成研究课程的指导- 密集的制度环境，将进一步推动我继续发展成为一名独立的研究员。

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.