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: 10053970
• 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/10053970
• 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; Epithelium; 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.

项目总结/摘要 急性肺损伤（Acute lung injury，ALI）是导致儿童急性呼吸窘迫综合征（acute respiratory distress Syndrome，ARDS）的主要原因 和成年人。在急性肺损伤中，肺微血管通透性过高引起肺水肿，导致氧合 ARDS的失败特征。目前，没有针对ARDS的特异性治疗，治疗是支持性的。 因此，需要更多地了解ALI机制，以开发潜在的治疗方法。 博士Rebecca Hough的研究旨在了解在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。霍夫医生 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（UCP 2）。UCP 2激活是微血管通透性过高所必需的， 肺水肿该建议使用活小鼠肺的显微镜。使用这种特殊的技术，博士。 Hough可以实时查看个体肺泡，观察肺损伤对线粒体的即时影响 在肺泡和微血管中。在这个建议中，霍夫博士将扩展她的研究，提出四个问题：（1） 长期的炎性损伤，如肺炎或大潮气量机械通气，是否会导致 以UCP 2依赖的方式发生屏障失效？(2)UCP 2在内皮细胞中的活化是肺损伤的基础吗 非肺部原因，如败血症？(3)氧化信号的方向性是否仅限于 肺泡到毛细血管，或者信号传导可以是双向的？（4）UCP 2是否是屏障失效的基础， 年轻人会出现严重的低氧血症吗 该提案详细说明了一项为期5年的研究计划，旨在为Hough博士提供一个独立的基础。 调查员霍夫博士将在杰出的导师指导下进行一个新颖的机械研究项目。 肺研究员Jahar Bhattacharya博士和著名的发育肺生物学家Dr. 惠灵顿卡多佐。她将（1）发展她在活鼠肺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）建立一个网络， 通过参加国家会议与合作者合作，以及（3）编写和提交一份独立的联邦 五年内研究经费。作为一名儿科重症监护医生，霍夫博士的目标是把她所学到的关于 UCP 2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