Purinergic Modulation of NKT Cells Ameliorates Hyperoxic Lung Injury

NKT 细胞的嘌呤能调节可改善高氧性肺损伤

• 批准号: 10162646
• 负责人: Dusan Hanidziar
• 金额: $ 17.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162646
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Acute; Acute Lung Injury; Adult Respiratory Distress Syndrome; Affect; Alveolar; Anesthesiology; Apoptosis; Applications Grants; Automobile Driving; Award; B-Lymphocytes; Cardiac Surgery procedures; Cell Count; Cells; Critical Care; Critical Illness; Cytometry; Cytotoxic T-Lymphocytes; Data; Development; Development Plans; Doctor of Philosophy; Endothelial Cells; Epithelial Cells; Evolution; Frequencies; Future; General Hospitals; Generations; Genetic; Goals; Growth Factor; Human; Hydrolysis; Hyperoxia; Immune; Immune response; Immune system; Immunology; Impairment; Infiltration; Inflammation; Inflammatory; Injury; International; Investigation; Laboratories; Lead; Leukocytes; Life; Link; Lung; Lung Inflammation; Lysophosphatidylcholines; Massachusetts; Mediating; Medicine; Mentors; Mentorship; Modeling; Mus; Natural Increases; Organ; Oxidative Stress; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Perioperative; Perioperative Care; Phenotype; Phospholipase; Phospholipids; Population; Predisposition; Production; Pulmonary Inflammation; Research; Research Personnel; Resistance; Role; Savings; Scientist; Signal Transduction; System; T-Lymphocyte; Testing; Texas; Therapeutic Agents; Thoracic Surgical Procedures; Time; Tissues; United States; United States National Institutes of Health; Universities; Up-Regulation; Wild Type Mouse; Work; alveolar epithelium; base; cancer immunotherapy; career; career development; cell growth; clinical application; clinically significant; extracellular; humanized mouse; in vivo; inflammatory milieu; inhibitor/antagonist; innovation; lipidomics; lung injury; lysophosphatidic acid; macrophage; medical schools; metabolomics; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; novel therapeutics; professor; programs; recruit; skills; success; translational approach; translational impact; translational model

High inspired concentrations of oxygen are commonly administered to critically ill patients or during perioperative management (especially in thoracic and cardiac surgery). However, increasing evidence suggests that pulmonary hyperoxia may promote inflammation, lung injury and worsen patient outcomes. Under the combined mentorship of Dr. Simon C. Robson, Professor of Medicine at Harvard Medical School, and Dr. Holger Eltzschig, Professor of Anesthesiology at University of Texas, the candidate will investigate novel therapeutic approaches to mitigate against acute hyperoxic lung inflammation. We have previously identified key roles for natural killer T cells (NKT) in mediating hyperoxic lung injury. Novel therapeutic approaches studied in this proposal are based on purinergic modulation of NKT cells and potentially other immune cells involved in lung injury, which we found can be achieved by targeting two closely related ectoenzymes CD39 (ENTPD1) and autotaxin (ENPP2). These approaches are operational, at least in part, by increasing levels of extracellular ATP (promoting NKT cell apoptosis) and/or decreasing levels of lysophosphatidic acid (LPA) which is a key NKT cell growth factor. We hypothesize that catalytic activities of these ectonucleotidases/phospholipases - CD39 and autotaxin - dictate recruitment of NKT and other immune cells that then cause alveolar injury by modulating the phospholipid- phosphonucleotide milieu. In the first aim, involvement of immune subsets in hyperoxic lung injury will be characterized by time of flight mass cytometry-CyTOF and systems immunology approaches. In the second aim, we will investigate the precise mechanisms by which CD39 and ATX targeting modulates lung injury. In the third aim, novel translational approaches of autotaxin and CD39 targeting in acute lung injury in vivo, including in humanized mouse model, will be studied. The candidate is an anesthesiologist and intensivist at Massachusetts General Hospital and is committed to the pursuit of an academic career in translational investigation. Mentorship by basic scientists and clinicians during this award will allow him to develop skills and expertise necessary to lead an independent research program. Pilot investigations of NKT and other invariant cells in patients with lung injury will be a component of career development plan and provide the basis of future grant applications. The candidate’s immediate goal to acquire robust research skills, as related to inflammation and acute lung injury, is reflected in the proposed research and in his choice of mentors and collaborators. The primary mentor, Dr. Simon C. Robson, MD PhD is a renowned international expert in inflammation and purinergic signaling. The co-mentor, Dr. Holger Eltzschig, MD PhD, is a leader in perioperative organ protection research and has worked with Dr. Robson over the past decade. Collaborators include Leo Otterbein, PhD (models of lung injury), James Lederer, PhD (CyTOF) and John Asara, PhD (metabolomics). Success with this NIH career development application will allow Dr. Hanidziar to develop an innovative research program, bridging immunology and critical care and to launch his career as a wholly independent investigator.

高吸入浓度的氧气通常用于重症患者或围手术期 管理（尤其是胸外科和心脏外科）。然而，越来越多的证据表明， 肺部高氧可能会促进炎症、肺损伤并使患者预后恶化。的共同 西蒙·C博士的指导。哈佛医学院医学教授罗布森和霍尔格·埃尔茨希格博士， 德克萨斯大学麻醉学教授，候选人将研究新的治疗方法 以减轻急性高氧肺炎。我们以前已经确定了自然杀手的关键作用 T细胞（NKT）介导高氧肺损伤。本提案中研究的新型治疗方法包括 基于NKT细胞和其他可能参与肺损伤的免疫细胞的嘌呤能调节，我们 发现可以通过靶向两种密切相关的胞外酶CD 39（ENTPD 1）和autotaxin（ENPP 2）来实现。 这些方法是可操作的，至少部分地，通过增加细胞外ATP的水平（促进NKT细胞增殖）。 细胞凋亡）和/或降低溶血磷脂酸（LPA）的水平，溶血磷脂酸是关键的NKT细胞生长因子。我们 假设这些外核苷酸酶/磷脂酶-CD 39和自分泌运动因子-支配催化活性 募集NKT和其他免疫细胞，然后通过调节磷脂- 磷酸核苷酸环境。在第一个目标中，免疫亚群在高氧肺损伤中的参与将是 通过飞行时间质谱细胞术-CyTOF和系统免疫学方法表征。在第二 我们将研究CD 39和ATX靶向调节肺损伤的确切机制。在 第三个目标，体内急性肺损伤中自分泌运动因子和CD 39靶向的新翻译方法，包括 在人源化小鼠模型中，将进行研究。候选人是一名麻醉师和重症监护医师， 马萨诸塞州总医院，并致力于追求学术生涯的翻译 调查在此期间，基础科学家和临床医生的指导将使他能够发展技能， 领导独立研究项目所需的专业知识。NKT和其他不变量的初步研究 细胞肺损伤患者将成为职业发展计划的一个组成部分，并提供未来的基础 补助金申请。候选人的直接目标是获得与炎症相关的强大研究技能 和急性肺损伤，反映在拟议的研究和他的导师和合作者的选择。的 主要导师西蒙·C博士Robson，MD PhD是国际知名的炎症和嘌呤能专家 发信号。共同导师Holger Eltzschig博士，医学博士，是围手术期器官保护研究的领导者 在过去的十年里一直与罗布森博士合作合作者包括Leo Otterbein博士（ 肺损伤），James Lederer博士（CyTOF）和John Asara博士（代谢组学）。在NIH事业上的成功 开发应用程序将允许Hanidziar博士开发一个创新的研究计划， 免疫学和重症监护，并开始他的职业生涯作为一个完全独立的调查员。