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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

基本信息

批准号：
10615634
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615634
关键词：
ATP Hydrolysis ATP phosphohydrolase Acute Acute Lung Injury Acute Respiratory Distress Syndrome Affect Alveolar Alveolus 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 Lysophosphatidylcholines Macrophage Massachusetts Mediating Medicine Mentors Mentorship Modeling Mus Organ Oxidative Stress Oxygen Pathway interactions Patient-Focused Outcomes Patients Perioperative Perioperative Care Phenotype Phospholipase Phospholipids Population Predisposition Production Proliferating Pulmonary Inflammation Research Research Personnel Resistance Role Scientist Signal Transduction System T-Lymphocyte Testing Texas Therapeutic Agents Thoracic Surgical Procedures Time Tissues Translational Research United States United States National Institutes of Health Universities Up-Regulation Wild Type Mouse Work alveolar epithelium cancer immunotherapy career career development cell growth clinical application clinically significant ecto-nucleotidase extracellular humanized mouse in vivo inflammatory milieu inhibitor innovation lipidomics lung injury lysophosphatidic acid medical schools metabolomics mortality mouse model neutrophil novel novel therapeutic intervention novel therapeutics professor programs recruit skills success translational approach translational impact translational model translational potential

项目摘要

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.

吸入高浓度氧气通常用于危重病人或围手术期。管理(尤其是胸部和心脏外科手术)。然而，越来越多的证据表明肺高氧可促进炎症、肺损伤和恶化患者的预后。在合并后的哈佛医学院医学教授西蒙·C·罗布森博士和霍尔格·埃尔茨希格博士的指导，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手的关键角色 T细胞(NKT)在高氧性肺损伤中的作用这项提案中研究的新治疗方法包括基于NKT细胞和可能参与肺损伤的其他免疫细胞的嘌呤能调节，我们发现可以通过靶向两个密切相关的胞外酶CD39(ENTPD1)和自体趋化蛋白(ENPP2)来实现。这些方法是可行的，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NKT细胞的关键生长因子。我们假设这些胞外核苷酸酶/磷脂酶-CD39和自体趋化蛋白-的催化活性决定了 NKT和其他免疫细胞的招募，然后通过调节磷脂- 磷酸核苷酸环境。在第一个目标中，免疫亚群参与高氧性肺损伤以飞行时间质量细胞术和系统免疫学方法为特征。在第二个目的：探讨CD39和ATX靶向调控肺损伤的确切机制。在第三个目标，体内急性肺损伤中自体趋化因子和CD39靶向的新的翻译方法，包括在人性化的小鼠模型中，将对其进行研究。这位候选人是一名麻醉师和重症医生。马萨诸塞州总医院，致力于在翻译领域追求学术生涯调查。在此奖项期间，基础科学家和临床医生的指导将使他能够发展技能和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调查肺损伤患者的细胞将成为职业发展计划的一个组成部分，并为未来提供基础批准申请。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对导师和合作者的选择上。这个主要导师西蒙·C·罗布森博士，医学博士，国际知名炎症和嘌呤能专家发信号。共同导师，医学博士霍尔格·埃尔茨希格，是围手术期器官保护研究的领导者在过去的十年里，他一直与罗布森博士合作。合作者包括Leo Otterbein，PhD(模特肺损伤)、詹姆斯·莱德尔博士(CyTOF)和约翰·阿萨拉博士(代谢组学)。在NIH的职业生涯中取得成功开发应用程序将使Hanidziar博士能够开发一项创新的研究计划，桥接他的职业生涯是一名完全独立的调查员。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In Response.

在回应中。

DOI：
10.1097/mcg.0000000000000451
发表时间：
2016
期刊：
Journal of clinical gastroenterology
影响因子：
2.9
作者：
Dasarathy,Srinivasan;Dasarathy,Jaividhya;Khiyami,Amer;Yerian,Lisa;McCullough,ArthurJ
通讯作者：
McCullough,ArthurJ

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