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: 10443725
• 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/10443725
• 关键词: Acids; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; 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.

项目概要/摘要 急性肺损伤 (ALI) 会导致急性呼吸窘迫综合征 (ARDS)，对儿童来说是致命的 和成人。在 ALI 中，肺微血管通透性过高会导致肺水肿，从而导致氧合 ARDS 的故障特征。目前，ARDS 尚无特效疗法，治疗主要为支持性治疗。 因此，需要更多地了解 ALI 机制，以便开发潜在的治疗方法。 Rebecca Hough 博士的研究旨在了解 ALI 中有害信号是如何传达的 从肺泡到微血管，导致微血管通透性过高和肺水肿。霍夫博士 发现微血管中的线粒体可以通过质子通道的氧化激活来感知损伤 解偶联蛋白 2 (UCP2)。 UCP2 激活对于微血管通透性过高是必要的 肺水肿。该提案使用活体小鼠肺部的显微镜检查。使用这种专门技术，博士。 Hough可以实时查看单个肺泡，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，霍夫博士将扩展她的研究，提出四个问题：(1) 长期炎症损伤（例如肺炎或高潮气量机械通气）是否会导致 屏障以 UCP2 依赖性方式失效？； (2) 内皮UCP2激活是否是肺损伤的基础 来自非肺部原因，例如败血症？； (3) 氧化信号是否有专门的方向性？ 肺泡到毛细血管，或者信号传导可以是双向的吗？ (4) UCP2 是否是屏障失效的原因？ 年轻人严重低氧血症？ 该提案详细介绍了一项为期 5 年的研究计划，旨在为霍夫博士作为独立研究人员奠定基础。 研究者。霍夫博士将在杰出的导师的指导下进行一项新颖的机械研究项目 肺部研究员 Jahar Bhattacharya 博士和著名肺发育生物学家 Dr. Jahar Bhattacharya 的共同指导。 威灵顿·卡多佐。她将 (1) 发展她在活体小鼠肺部实时荧光成像方面的专业知识 和来自已故捐赠者的人肺，以及肺损伤的动物模型，（2）建立一个网络 通过参加全国会议进行合作，以及 (3) 准备并提交独立的联邦 5年内的研究补助金。作为一名儿科重症监护医生，霍夫医生的目标是利用她所学到的知识 UCP2 及其在与 ARDS 相关的屏障衰竭中的重要性，并将这些知识应用于婴儿和 孩子们。