The role of innate immunity in the traumatic brain injury-induced immune suppression syndrome

先天免疫在脑外伤引起的免疫抑制综合征中的作用

基本信息

批准号：
9334278
负责人：
STEVEN J SCHWULST
金额：
$ 19.01万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-20 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334278
关键词：
Acute Address Affect American Animals Anti-Inflammatory Agents Anti-inflammatory Antibody Formation Apoptosis Automobile Driving Award Belief Biological Assay Biology Blood Book Chapters Brain Brain Injuries Cause of Death Cell Count Cells Centers for Disease Control and Prevention (U.S.)Chronic Closed head injuries Core Facility Critical Care Data Development Dichloromethylene Diphosphonate Disease Employee Strikes Encapsulated Environment Expenditure Fellowship Flow Cytometry Funding Generations Goals Healthcare Hour ITGAM gene Immune Immune System Diseases Immune System and Related Disorders Immune response Immunologist Immunology Immunosuppression Immunosuppressive Agents Impaired cognition Impairment Individual Infection Infiltration Injection of therapeutic agent Injury Innate Immune Response Innate Immune System Intervention Knock-out Knowledge Laboratories Lasers Legal patent Link Liposomes Lymphocyte Magnetism Manuscripts Mediating Mentored Clinical Scientist Award Mentors Mentorship Microglia Modeling Modernization Monoclonal Antibodies Mus Myelogenous NR4A1 gene Natural Immunity Nature Nerve Degeneration Neuraxis Neurologic Neurosciences Operative Surgical Procedures Pathogenesis Peripheral Phagocytosis Phenotype Play Pneumonia Population Predisposition Process Publishing Research Residencies Role Science Scientist Seasons Secondary to Sepsis Series Source Surgeon Syndrome Testing Therapeutic Time Tissues Training Training Programs Trauma Traumatic Brain Injury Universities Washington White Blood Cell Count procedure Work animal facility career cell type clinical application combat cytokine experimental study flexibility immune function inflammatory milieu interest macrophage monocyte mortality mouse model neuroimmunology neurotropic neutrophil novel therapeutics professor public health relevance relating to nervous system repaired response secondary infection

项目摘要

DESCRIPTION (provided by applicant): Candidate: Dr. Schwulst is a trauma/critical care surgeon and Assistant Professor of Surgery at Northwestern University. He completed his general surgery residency, trauma/critical care fellowship, and research fellowship at Washington University, St. Louis. During his research fellowship, Dr. Schwulst studied the programmed cell death of lymphocytes during sepsis in the laboratory of Richard Hotchkiss. Since that time, Dr. Schwulst has published twelve manuscripts, three book chapters, numerous abstracts, and been awarded a US patent. His current career goals are to further advance the science behind injury with a particular focus on the innate immune response to traumatic brain injury (TBI). His long-term goal is to become a seasoned surgeon-scientist with both a fully funded laboratory and a robust trauma surgery and critical care practice. Environment: Northwestern University provides a comprehensive, interdisciplinary training program in modern immunology. Trainees are provided with flexibility to pursue individual research interests with strong mentorship from seasoned immunologists in diverse research fields. There are numerous immunology core facilities at Northwestern along with a state of the art animal facility. Additionally, his mentor's laboratory has its own 4-laser LSRII flow cytometer and 4 column Miltenyi magnetic separator. Research: TBI results in immune suppression leaving the host susceptible to secondary infection. In fact, infection is the leading cause of death following TBI. Preliminary data has shown that TBI results in a rapid and sustained loss of cells from the innate immune system as well as a shift towards an anti-inflammatory phenotype. Taken together, we hypothesize that monocytes and macrophages initiate the pathogenesis of TBI-induced immune dysfunction by creating and driving a systemic anti-inflammatory milieu resulting in increased infectious mortality after TBI. To test this hypothesis we have created a clinically applicable murine model of closed head injury to specifically interrogate the peripheral immune response to TBI. We aim to determine the role of monocytes and macrophages in the development of TBI-induced immune suppression, whether TBI drives the innate immune response towards an anti-inflammatory phenotype, and whether depletion of monocytes and macrophages decreases the susceptibility to secondary infections after TBI. To further these aims we will fully characterize the immune phenotype induced by our model via flow cytometry, cytokine analysis, and antibody production. Additionally, we will employ a series of monocyte/macrophage depletion experiments to further dissect their role in this process as well as a series of survival studies to determine if manipulation of the monocyte and macrophage populations affects the susceptibility of brain-injured animals to secondary pneumonia. Lastly, the effect of monocyte/macrophage depletion on cortical loss and neuronal degeneration after TBI will be assessed.

描述（由适用提供）：候选人：Schwulst博士是西北大学的创伤/重症监护外科医生和外科助理教授。他在圣路易斯华盛顿大学完成了一般手术住所，创伤/重症监护奖学金和研究奖学金。在研究奖学金期间，施沃斯特博士在理查德·霍奇基斯（Richard Hotchkiss）实验室的败血症期间研究了淋巴细胞的程序性细胞死亡。从那时起，施沃斯特博士出版了十二本手稿，三本书章节，众多摘要，并获得了美国专利。他目前的职业目标是进一步推进受伤背后的科学，特别关注对创伤性脑损伤（TBI）的先天免疫反应。他的长期目标是成为经验丰富的外科医生科学家，并拥有全额资助的实验室和强大的创伤手术和重症监护实践。环境：西北大学提供了现代免疫学方面的全面，跨学科的培训计划。为受训者提供了灵活性，可以从潜水员研究领域的经验丰富的免疫学家那里购买具有强烈心态的个人研究兴趣。西北部有许多免疫学核心设施以及最先进的动物设施。此外，他的心态实验室具有自己的4射线LSRII流式细胞仪和4列Miltenyi磁性分离器。研究：TBI导致免疫抑制，使宿主容易受到继发感染的影响。实际上，感染是TBI后死亡的主要原因。初步数据表明，TBI导致先天免疫系统的细胞快速损失，以及向抗炎表型转移。综上所述，我们假设单核细胞和巨噬细胞通过创建和驱动系统性的抗炎环境，从而启动TBI诱导的免疫功能的发病机理，从而在TBI后增加感染性死亡率。为了检验这一假设对TBI的免疫反应。我们旨在确定单核细胞和巨噬细胞在TBI诱导的免疫抑制发展中的作用，TBI是否可以驱动对抗炎表型的先天免疫反应，以及单核细胞和巨噬细胞的耗竭是否会降低TBI后二级感染的易感性。为了进一步，我们将通过流式细胞术，细胞因子分析和抗体产生来充分表征模型引起的免疫表型。此外，我们将采用一系列单核细胞/巨噬细胞部署实验，以进一步剖析其在此过程中的作用以及一系列生存研究，以确定对单核细胞和巨噬细胞种群的操纵是否会影响脑部受损的动物对次生肺炎的敏感性。最后，将评估单核细胞/巨噬细胞部署对TBI后皮质损失和神经元变性的影响。