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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：
9012910
负责人：
STEVEN J SCHWULST
金额：
$ 19.22万
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/9012910
关键词：
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.)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 response Immune system Immunologist Immunology Immunosuppression Immunosuppressive Agents Impaired cognition Impairment Individual Infection Infiltration Injection of therapeutic agent Injury Intervention Knock-out Knowledge Laboratories Lasers Lead Left Legal patent Link Liposomes Lymphocyte Magnetism Manuscripts Mediating Mentored Clinical Scientist Award Mentors Mentorship Microglia Modeling 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 Time Tissues Training Training Programs Trauma Traumatic Brain Injury Universities Washington White Blood Cell Count procedure Work abstracting animal facility career cell type combat cytokine flexibility immune function injured interest macrophage monocyte mortality neuroimmunology neurotropic neutrophil professor public health relevance relating to nervous system repaired research study 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(由申请人提供)：应聘者：施武斯特博士是西北大学创伤/重症监护外科医生和外科助理教授。他在圣路易斯的华盛顿大学完成了普通外科住院医师、创伤/重症监护研究员和研究研究员的工作。在担任研究员期间，施武斯特博士在理查德·霍奇基斯的实验室里研究了脓毒症期间淋巴细胞的程序性细胞死亡。从那时起，施武斯特博士已经发表了12篇手稿，3本书的章节，无数的摘要，并被授予美国专利。他目前的职业目标是进一步推进损伤背后的科学，特别关注创伤性脑损伤(TBI)的先天免疫反应。他的长期目标是成为一名经验丰富的外科医生兼科学家，拥有一个资金充足的实验室，以及强大的创伤手术和危重护理实践。环境：西北大学提供现代免疫学的综合跨学科培训课程。学员可以灵活地追求个人的研究兴趣，并得到不同研究领域经验丰富的免疫学家的大力指导。西北大学有许多免疫学核心设施，以及最先进的动物设施。此外，他导师的实验室拥有自己的4激光LSRII流式细胞仪和4柱Miltenyi磁选机。研究：脑损伤会导致免疫抑制，使宿主容易受到二次感染。事实上，感染是脑外伤后死亡的主要原因。初步数据显示，脑外伤会导致先天免疫系统细胞的快速和持续丧失，并向抗炎表型转变。综上所述，我们假设，单核细胞和巨噬细胞通过创造和驱动全身抗炎环境，导致脑创伤后感染死亡率增加，从而启动了脑创伤后免疫功能障碍的发病机制。为了验证这一假设，我们建立了一种临床适用的闭合性脑损伤小鼠模型，专门询问外周对脑损伤的免疫反应。我们的目的是确定单核细胞和巨噬细胞在脑创伤后免疫抑制中的作用，脑损伤是否推动先天免疫反应向抗炎表型转变，以及单核细胞和巨噬细胞的耗竭是否降低脑损伤后继发感染的易感性。为了进一步实现这些目标，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我们的模型诱导的免疫表型。此外，我们将利用一系列单核/巨噬细胞耗竭实验进一步剖析它们在这一过程中的作用，以及一系列生存研究，以确定单核细胞和巨噬细胞种群的操纵是否会影响脑损伤动物对继发性肺炎的易感性。最后，将评估单核/巨噬细胞耗竭对脑创伤后皮质丢失和神经元变性的影响。