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：
10664829
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/10664829
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 biology Chest Clinical Clinical Research Clinical Trials Closure by clamp Collaborations Color Critical Care Cryopreservation Cytometry Data Disease Endothelium Epithelium 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 Institution Interferon Type II International Intervention Intervention Trial Ischemia Ischemic Stroke Laboratory Scientists Ligands Lung Lung Transplantation Lung diseases Macrophage 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 lung allograft lung injury lung ischemia 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 Daniel Calabrese 博士的 BLRD CDA-2 奖项申请，他是 SFVA 的主治医师和加州大学旧金山分校肺科和重症监护科助理教授他正在将自己定位为急性肺损伤免疫学临床研究的研究者。这 CDA-2 奖项将为 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自然杀伤细胞、其受体及其配体的了解 (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介入试验奠定机制基础；(4) 建立一个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。为了实现这些为了实现这一目标，卡拉布雷斯博士组建了一个指导团队，其中包括他的主要导师约翰·格陵兰博士、肺免疫学和肺损伤领域的国际专家，以及高级联合导师 Mary Nakamura 博士胸部缺血再灌注损伤（IRI）先天免疫反应专家。他已经建立了自己的职业生涯发展委员会和科学顾问委员会，另外还将包括：专家 Lewis Lanier 博士自然杀伤 (NK) 细胞生物学领域，拥有 50 多名学员和 250 篇出版物；马克鲁尼博士，先天专家急性肺损伤机制及小鼠肺移植模型；以及主任乔纳森·辛格博士加州大学旧金山分校肺移植研究项目的负责人，肺移植流行病学研究专家。此外，他还将获得博士的教程和科学建议。杰森·克里斯蒂、达拉·托格森、马修 Spitzer、Michael Matthay、Anatoly Urisman 在多机构合作、统计遗传学、质量方面分别是细胞计数、人肺实验模型和病理学。拟议的研究将扩大两种小鼠肺损伤模型和人类样本的强有力的初步数据显示了一个范例- NK 细胞在缺血再灌注损伤 (IRI) 中的作用发生转变。拟议的研究将检验假设 NK 细胞直接介导在实验和人类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达到以下具体目的： (1) 确定 NK 细胞如何被激活并诱导小鼠肺部 IRI (2) 确定 NK 细胞在小鼠肺部 IRI 期间如何转运至肺部 (3) 评估人IRI中NK细胞的活化。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，例如下一代流式细胞术和多重蛋白质定量以确定肺损伤后关键的先天免疫反应。这项研究是对于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疗法急性呼吸窘迫综合征、晚期肺病、心肌梗塞和中风等疾病。这这项工作很新颖，因为它将定义 NK 细胞受体和应激配体在 IRI 中的新作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Ribavirin to the Rescue: Natural Killer-Cell Function After Hepatitis C Virus Treatment in Liver Transplant Recipients.

利巴韦林的救援：肝移植受者丙型肝炎病毒治疗后的自然杀伤细胞功能。

DOI：
发表时间：
2021-10-01
期刊：
影响因子：
6.2
作者：
Calabrese; Daniel R
通讯作者：
Daniel R

Paradox of Power: Dynamic Tools to Predict Respiratory Failure in Spontaneously Breathing Patients.

权力悖论：预测自主呼吸患者呼吸衰竭的动态工具。

DOI：
发表时间：
2023-03-01
期刊：
影响因子：
8.8
作者：
Calabrese, Daniel R;London, Martin J
通讯作者：
London, Martin J

The Lung Allocation Score Remains Inequitable for Patients with Pulmonary Arterial Hypertension, Even after the 2015 Revision.

即使在 2015 年修订之后，肺动脉高压患者的肺部分配评分仍然不公平。

DOI：
发表时间：
2023-02-01
期刊：
影响因子：
24.7
作者：
Kolaitis, Nicholas A;Chen, Hubert;Calabrese, Daniel R;Kumar, Kerry;Obata, Jill;Bach, Carrie;Golden, Jeffrey A;Simon, Marc A;Kukreja, Jasleen;Hays, Steven R;Leard, Lorriana E;Singer, Jonathan P;De Marco, Teresa
通讯作者：
De Marco, Teresa