Natural killer cells in pulmonary ischemia-reperfusion injury

这是一份申请BLRD CDA-2奖的申请书，获奖者是SFVA的专职医生Daniel Calabrese博士和 加州大学旧金山分校肺科和重症监护科助理教授 世卫组织正在确立自己作为急性肺损伤免疫学临床研究人员的地位。这 CDA-2奖将为卡拉布雷斯博士提供必要的支持，以实现以下目标：(1) 提高对自然杀伤细胞及其受体及其配体在缺血再灌注损伤中的认识 (2)掌握鼠、人免疫学和生物信息学的理论和实践技能。(3)建立 未来改善肺损伤综合征的介入性试验的机制基础和(4)建立 独立基础实验室科学家的职业生涯专注于肺部疾病的先天免疫学。要实现这些目标 目标，卡拉布雷斯博士已经组建了一个指导团队，由他的主要导师约翰·格陵兰博士和 肺免疫学和肺损伤方面的国际专家，以及高级共同导师Mary Nakamura博士，以及 胸部缺血再灌注损伤(IRI)先天免疫反应方面的专家。他已经建立了自己的职业生涯 发展委员会和科学咨询委员会，额外成员：刘易斯·拉尼尔博士，专家 在自然杀伤(NK)细胞生物学方面，有50多名学员和250篇出版物；天然方面的专家马克·鲁尼博士 急性肺损伤的机制和肺移植的小鼠模型；乔纳森·辛格博士，主任 他是加州大学旧金山分校肺移植研究项目的负责人和肺移植流行病学研究的专家。 此外，他还将得到杰森·克里斯蒂博士、达拉·托格森博士、马修博士的指导和科学建议 斯皮策，迈克尔·马泰，阿纳托利·乌里斯曼在多机构合作，统计遗传学，麻省理工学院 细胞学、人肺实验模型和病理学。拟议中的研究将扩大 在两个肺损伤小鼠模型和人类样本中的强劲初步数据显示了一种范式- NK细胞在缺血再灌注损伤中的角色转换。这项拟议的研究将检验这一假设 NK细胞直接介导实验性和人肺缺血再灌注损伤 通过以下特定目的的受体特异性相互作用：(1)确定NK细胞如何被激活 并诱导小鼠肺IRI(2)，以确定在小鼠肺IRI期间NK细胞如何进入肺 (3)评价人脑缺血再灌注损伤中NK细胞的活性。这项工作具有创新性，因为这些研究将利用 先进的小鼠手术模型和尖端技术，如下一代流式细胞仪和 多重蛋白定量以确定肺损伤后的关键先天免疫反应。这项研究是 对退伍军人具有重要意义，因为它将确定在退伍军人健康特定领域使用的临床前和临床治疗 急性呼吸窘迫综合征、晚期肺部疾病、心肌梗死和中风。这 这项工作是新颖的，因为它将定义NK细胞受体和应激配体在IRI中的新角色。

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.