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: 9921483
• 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/9921483
• 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; 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 然而，越来越多的证据表明， 肺部高氧可能会促进炎症、肺损伤并导致患者预后恶化。 哈佛医学院医学教授 Simon C. Robson 博士和 Holger Eltzschig 博士的指导， 德克萨斯大学麻醉学教授候选人将研究新的治疗方法 减轻急性高氧性肺部炎症我们之前已经确定了自然杀伤剂的关键作用。 本提案中研究的 T 细胞 (NKT) 介导高氧性肺损伤的新治疗方法。 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 CD39 (ENTPD1) 和自分泌运动因子 (ENPP2) 来实现。 这些方法至少部分是通过增加细胞外 ATP 水平（促进 NKT 细胞 细胞凋亡）和/或降低溶血磷脂酸（LPA）水平，溶血磷脂酸是一种关键的 NKT 细胞生长因子。 这些核酸外切酶/磷脂酶的催化活性 - CD39 和自分泌运动因子 - 决定 NKT 和其他免疫细胞的募集，然后通过调节磷脂引起肺泡损伤 在第一个目标中，免疫亚群参与高氧性肺损伤。 第二个特点是飞行时间质谱流式细胞仪-CyTOF 和系统免疫学方法。 目标是，我们将研究 CD39 和 ATX 靶向调节肺损伤的精确机制。 第三个目标，自分泌运动因子和 CD39 靶向体内急性肺损伤的新转化方法，包括 在人源化小鼠模型中，将对该候选人进行研究。 马萨诸塞州总医院致力于追求转化方面的学术生涯 基础科学家的指导和获奖期间的调查将使他能够发展技能和能力。 领导独立研究项目所需的专业知识。 肺损伤患者的细胞将成为职业发展计划的组成部分，并为未来提供基础 候选人的近期目标是获得与炎症相关的强大研究技能。 和急性肺损伤，反映在拟议的研究以及他对导师和合作者的选择中。 主要导师 Simon C. Robson 博士，医学博士，国际著名炎症和嘌呤能专家 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。 过去十年与 Robson 博士合作，合作者包括 Leo Otterbein 博士（模型）。 肺损伤），James Lederer 博士（CyTOF）和 John Asara 博士（代谢组学）在 NIH 职业生涯中取得了成功。 开发应用程序将使 Hanidziar 博士能够开发一个创新的研究项目， 免疫学和重症监护，并以完全独立的研究者的身份开始了他的职业生涯。