Natural killer cells in pulmonary ischemia-reperfusion injury

自然杀伤细胞在肺缺血再灌注损伤中的作用

基本信息

批准号：
10374050
负责人：
Daniel Calabrese
金额：
--
依托单位：
VETERANS AFFAIRS MED CTR SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374050
关键词：
Activated Natural Killer Cell Acute Lung Injury Acute Respiratory Distress Syndrome Allografting Antibodies Area Award Bioinformatics Blood Cells Bronchoalveolar Lavage Fluid CCR5 gene CXCR3 gene California Cell Maturation Cell surface Cells Cellular Stress Cellular biology Chest Clinical Clinical Research Clinical Trials Closure by clamp Collaborations Color Critical Care Cryopreservation Cytometry Data Disease Endothelium Epithelial Experimental Models Flow Cytometry Foundations Frequencies Functional disorder Funding Future Genetic Goals Greenland Health Hilar Human Hypoxia Immune Immunity Immunodeficient Mouse Immunology Individual Inflammatory Bowel Diseases Injury Innate Immune Response Interferon Type II International Intervention Intervention Trial Ischemia Ischemic Stroke Laboratory Scientists Lead Ligands Lung Lung Transplantation Lung diseases Measures Mediating Mentors Mentorship Mission Modality Modeling Monoclonal Antibodies Mus Myocardial Infarction NK Cell Activation Natural Killer Cells Neutrophil Infiltration Nonpenetrating Wounds Outcome PTPRC gene Pathology Pathway interactions Patients Phenotype Physicians Process Proteins Publications Receptor Cell Receptor Signaling Reperfusion Injury Reperfusion Therapy Research Research Personnel Risk Role Sampling San Francisco Series Stress Stroke Surgical Models Syndrome Technology Testing Time Tissues Transplant Recipients Transplantation Universities Veterans Warm Ischemia Wild Type Mouse Work candidate selection career career development chemokine chemokine receptor cohort cytokine cytotoxicity epidemiology study experience graft dysfunction human disease human model improved innate immune mechanisms innovation ischemic injury lung allograft lung injury lung ischemia macrophage monocyte mouse model new therapeutic target next generation novel novel therapeutics perforin peripheral blood pre-clinical professor programs prospective receptor reconstitution response skill acquisition skills trafficking translational scientist

项目摘要

This is an application for a BLRD CDA-2 award for Dr. Daniel Calabrese, a staff physician at the SFVA and an Assistant Professor in the Division of Pulmonary and Critical Care at the University of California, San Francisco who is establishing himself as an investigator in clinical research into the immunology of acute lung injury. This CDA-2 award will provide Dr. Calabrese with the necessary support to accomplish the following goals: (1) to improve the understanding of natural killer cells, their receptors, and their ligands in ischemia-reperfusion injury (2) to acquire theoretical and practical skills in mouse and human immunology and bioinformatics (3) to establish mechanistic foundations for future interventional trials to improve lung injury syndromes and (4) to establish an independent basic laboratory scientist career focused on innate immunology in lung disease. To achieve these goals, Dr. Calabrese has assembled a mentoring team consisting of his primary mentor, Dr. John Greenland, an international expert in pulmonary immunology and lung injury, and a senior co-mentor Dr. Mary Nakamura, an expert in the innate immune response to thoracic ischemia-reperfusion injury (IRI). He has assembled a career development committee and scientific advisory board that will additionally consist of: Dr. Lewis Lanier, an expert in natural killer (NK) cell biology with over 50 mentees and 250 publications; Dr. Mark Looney, an expert in innate mechanisms of acute lung injury and mouse models of lung transplantation; and, Dr. Jonathan Singer, director of the UCSF lung transplant research program and an expert in lung transplant epidemiology research. Additionally, he will have tutorials and scientific advice from Drs. Jason Christie, Dara Torgerson, Matthew Spitzer, Michael Matthay, Anatoly Urisman in multi-institutional collaboration, statistical genetics, mass cytometry, human lung experimental models, and pathology, respectively. The proposed research will expand on strong preliminary data in two mouse models of lung injury and human samples showing a paradigm- shifting role for NK cells in ischemia-reperfusion injury (IRI). The proposed study will test the hypothesis that NK cells directly mediate the lung injury observed in experimental and human ischemia-reperfusion injury through receptor-specific interactions in the following specific aims: (1) To determine how NK cells are activated and induce mouse pulmonary IRI (2) To determine how NK cells traffic to the lung during mouse pulmonary IRI (3) To evaluate NK cell activation in human IRI. This work is innovative as these studies will make use of advanced mouse surgical models and cutting-edge technologies such as next generation flow cytometry and multiplex protein quantification to define a key innate immune response following lung injury. This research is significant for veterans as it will identify pre-clinical and clinical therapies to use in veteran-health specific diseases of acute respiratory distress syndrome, advanced lung disease, myocardial infarction, and stroke. This work is novel as it will define a new role of NK cell receptors and stress ligands in IRI.

这是为Daniel Calabrese博士颁发的BLRD CDA-2奖，SFVA的工作人员加利福尼亚大学旧金山分校的肺和重症监护系助理教授他正在担任急性肺损伤免疫学临床研究的研究者。这 CDA-2奖将为Calabrese博士提供必要的支持，以实现以下目标：（1）提高对缺血再灌注损伤中天然杀伤细胞，其受体和配体的理解（2）获得老鼠和人类免疫学和生物信息学的理论和实践技能（3）建立未来介入试验的机械基础，以改善肺损伤综合征，（4）建立独立的基本实验室科学家职业专注于肺部疾病中的先天免疫学。实现这些目标，卡拉布雷斯博士组建了一个指导团队，由他的主要导师约翰·格林兰博士组成国际肺免疫学和肺部损伤专家，以及高级联合收取者玛丽·纳卡穆拉（Mary Nakamura）博士，对胸部缺血再灌注损伤的先天免疫反应的专家（IRI）。他已经聚集了职业开发委员会和科学顾问委员会还将包括：专家刘易斯·拉尼尔博士在天然杀手（NK）细胞生物学中，有50多名受训者和250个出版物；先天专家马克·鲁尼（Mark Looney）博士急性肺损伤的机制和肺移植的小鼠模型；而且，导演乔纳森·辛格（Jonathan Singer）博士 UCSF肺移植研究计划和肺移植流行病学研究专家。此外，他还将提供博士的教程和科学建议。杰森·克里斯蒂（Jason Christie），达拉·托格森（Dara Torgerson），马修 Spitzer，Michael Matthay，Anatoly Urisman在多机构合作，统计遗传学，群众细胞仪，人肺实验模型和病理学分别。拟议的研究将扩大在两种肺损伤的小鼠模型和人类样品模型中，显示出范式 - NK细胞在缺血再灌注损伤（IRI）中的转移作用。拟议的研究将检验假设 NK细胞直接介导实验和人缺血 - 再灌注损伤中观察到的肺损伤通过以下特定目的中的受体特异性相互作用：（1）确定如何激活NK细胞并诱导小鼠肺IRI（2）来确定小鼠肺IRI期间NK细胞如何流向肺（3）评估人IRI中的NK细胞激活。这项工作具有创新性，因为这些研究将利用高级小鼠手术模型和最先进的技术，例如下一代流式细胞仪和多重蛋白质定量以定义肺损伤后关键的先天免疫反应。这项研究是对于退伍军人而言，这将确定临床前和临床疗法以用于退伍军人健康特异性急性呼吸窘迫综合征，晚期肺部疾病，心肌梗塞和中风的疾病。这工作是新颖的，因为它将定义IRI中NK细胞受体和应激配体的新作用。