Natural killer cells in pulmonary ischemia-reperfusion injury

这是一份申请BLRD CDA-2奖的申请，申请人是丹尼尔卡拉布雷斯博士，他是SFVA的一名医生， 加州大学旧金山弗朗西斯科肺部和重症监护科助理教授 他是急性肺损伤免疫学临床研究的研究者。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） 提高对缺血再灌注损伤中自然杀伤细胞及其受体和配体的认识 (2)获得小鼠和人类免疫学和生物信息学的理论和实践技能（3）建立 为未来改善肺损伤综合征的干预性试验奠定了机制基础;（4）建立一个 独立基础实验室科学家职业生涯专注于肺部疾病的先天免疫学。实现这些 目标，卡拉布雷斯博士组建了一个指导小组，由他的主要导师，约翰格陵兰博士， 肺免疫学和肺损伤的国际专家，以及高级共同导师玛丽中村博士， 在胸部缺血再灌注损伤（IRI）的先天免疫反应方面的专家。他已经有了一份事业 发展委员会和科学咨询委员会，将另外包括：刘易斯拉尼尔博士，专家 在自然杀伤（NK）细胞生物学与50多名学员和250出版物;马克鲁尼博士，在先天性 急性肺损伤的机制和肺移植的小鼠模型;以及，Jonathan Singer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，也是肺移植流行病学研究的专家。 此外，他将有教程和科学建议博士贾森克里斯蒂，达拉托格森，马修 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，质量 细胞术、人肺实验模型和病理学。这项研究将扩大 两个小鼠肺损伤模型和人类样本的初步数据显示， NK细胞在缺血-再灌注损伤（IRI）中的作用改变。拟议中的研究将检验这一假设 NK细胞直接介导在实验性和人缺血再灌注损伤中观察到的肺损伤 通过受体特异性相互作用，实现以下特定目的：（1）确定NK细胞如何被激活 （2）观察NK细胞在小鼠肺IRI过程中向肺的转运 (3)目的：评价NK细胞在人IRI中的活化作用。这项工作是创新的，因为这些研究将利用 先进的小鼠手术模型和尖端技术，如下一代流式细胞术， 多重蛋白质定量以确定肺损伤后的关键先天免疫应答。本研究是 对退伍军人来说意义重大，因为它将确定用于退伍军人健康特定的临床前和临床治疗方法。 急性呼吸窘迫综合征、晚期肺病、心肌梗塞和中风的疾病。这 这项工作是新颖的，因为它将确定NK细胞受体和应激配体在IRI中的新作用。

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.