Mitochondrial mechanisms underlying alveolar-capillary barrier regulation

肺泡毛细血管屏障调节的线粒体机制

• 批准号: 10217240
• 负责人: Rebecca Frances Hough
• 金额: $ 16.55万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10217240
• 关键词: Acids; Acute Lung Injury; Adult; Adult Respiratory Distress Syndrome; Alveolar; Alveolar wall; Alveolus; Animal Model; Blood; Blood Vessels; Blood capillaries; Cell Communication; Cells; Characteristics; Child; Childhood; Deterioration; Development; Disease; Edema; Endothelium; Epithelial; Event; Exposure to; Failure; Foundations; Glycolysis; Goals; Hour; Human; Hydrogen Peroxide; Hypoxemia; Imaging Techniques; Impairment; In Situ; Individual; Infant; Inflammatory; Infusion procedures; Injury; Knowledge; Lipopolysaccharides; Liquid substance; Lung; Mechanical ventilation; Membrane; Mentorship; Metabolic; Metabolism; Microscopy; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Pediatric Acute Lung Injury; Pneumonia; Production; Property; Protons; Pulmonary Edema; Reactive Oxygen Species; Regulation; Research; Research Personnel; Research Project Grants; Role; Secondary to; Sepsis; Severities; Signal Transduction; Syndrome; Techniques; Therapeutic; Tidal Volume; Time; UCP2 protein; alveolar epithelium; career; design; fluorescence imaging; follow-up; interstitial; lung development; lung injury; meetings; mortality; novel; response; targeted treatment

Project Summary / Abstract Acute Lung Injury (ALI) leads to the Acute Respiratory Distress Syndrome (ARDS), which is deadly to children and adults. In ALI, lung microvascular hyperpermeability causes pulmonary edema, leading to oxygenation failure characteristic of ARDS. Currently, there is no specific therapy for ARDS and treatment is supportive. Thus, there is a need for more understanding of ALI mechanisms in order to develop potential therapeutics. Dr. Rebecca Hough’s research is aimed at understanding how, in ALI, an injurious signal is communicated from alveoli to microvessels, resulting in microvascular hyperpermeability and pulmonary edema. Dr. Hough has found that mitochondria in microvessels can sense injury through oxidative activation of the proton channel uncoupling protein 2 (UCP2). UCP2 activation is necessary for microvascular hyperpermeability and pulmonary edema. This proposal uses microscopy of live mouse lungs. Using this specialized technique, Dr. Hough can view individual alveoli in real-time and observe the immediate effects of lung injury on mitochondria in alveoli and microvessels. In this proposal, Dr. Hough will expand her research to ask four questions: (1) Does a prolonged inflammatory injury, such as pneumonia or high tidal volume mechanical ventilation, cause barrier failure in a UCP2-dependent manner?; (2) Does UCP2 activation in endothelium underlie lung injury from non-pulmonary causes, such as sepsis?; (3) Is there a directionality of oxidative signaling exclusively from alveolus to capillary, or can the signaling be bidirectional?; and (4) Does UCP2 underlie barrier failure and severe hypoxemia in the young? This proposal details a 5-year research plan designed to give Dr. Hough a foundation as an independent investigator. Dr. Hough will conduct a novel mechanistic research project under the mentorship of outstanding lung researcher Dr. Jahar Bhattacharya, and the co-mentorship of renowned development lung biologist Dr. Wellington Cardoso. She will (1) develop her expertise in real-time fluorescence imaging of live mouse lungs and human lungs from deceased donors, as well as animal models of lung injury, (2) build a network of collaborators via participation at national meetings, and (3) prepare and submit an independent federal research grant within 5 years. As a pediatric intensivist, Dr. Hough aims to take what she has learned about UCP2 and its importance in barrier failure associated with ARDS and apply this knowledge to infants and children.

项目摘要/摘要 急性肺损伤(ALI)导致急性呼吸窘迫综合征(ARDS)，对儿童来说是致命的 和成年人。在ALI中，肺微血管高通透性导致肺水肿，导致氧合。 ARDS的故障特征。目前，ARDS还没有特效的治疗方法，治疗是支持性的。 因此，有必要更多地了解ALI的机制，以开发潜在的治疗方法。 丽贝卡·霍夫博士的研究旨在了解在ALI中，伤害性信号是如何传递的 从肺泡到微血管，导致微血管高通透性和肺水肿。霍夫博士 已经发现，微血管中的线粒体可以通过氧化激活质子通道来感知损伤 解偶联蛋白2(UCP2)。UCP2激活是微血管高通透性所必需的 肺水肿。这项提议使用的是活鼠肺的显微镜。使用这项专门的技术，Dr。 Hough可以实时查看单个肺泡，并观察肺损伤对线粒体的即时影响 在肺泡和微血管中。在这项提案中，霍夫博士将扩大她的研究范围，提出四个问题：(1) 长时间的炎症性损伤，如肺炎或高潮气量机械通气，是否会导致 UCP2依赖的屏障功能障碍？；(2)内皮细胞UCP2激活是否导致肺损伤 非肺源性原因，如败血症？(3)氧化信号是否具有方向性 肺泡到毛细血管，或者信号可以是双向的？(4)UCP2是屏障失败和 年轻人出现严重的低氧血症？ 这份提案详细说明了一项为期5年的研究计划，旨在让霍夫博士成为一个独立的基金会 调查员。霍夫博士将在卓尔不群的指导下进行一项新的机械研究项目 肺研究人员Jahar Bhattacharya博士和著名发育肺生物学家Dr。 惠灵顿·卡多佐。她将(1)发展她在活鼠肺的实时荧光成像方面的专业知识 和来自已故捐赠者的人类肺，以及肺损伤的动物模型，(2)建立 协作者通过参加国家会议，以及(3)准备和提交独立的联邦 5年内获得研究资助。作为一名儿科重症医生，霍夫博士的目标是将她所学到的知识 UCP2及其在ARDS相关屏障衰竭中的重要性，并将这一知识应用于婴儿和 孩子们。