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

 描述（由申请人提供）：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普通外科住院医师、创伤/重症监护奖学金和研究奖学金。在他的研究奖学金期间，Schwulst博士在Richard霍奇基斯的实验室研究了脓毒症期间淋巴细胞的程序性细胞死亡。从那时起，Schwulst博士已经出版了12篇手稿，三本书的章节，许多摘要，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科学家，拥有一个资金充足的实验室和一个强大的创伤手术和重症监护实践。环境：西北大学提供现代免疫学的全面，跨学科的培训计划。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有力指导。有许多免疫学的核心设施在西北沿着与最先进的动物设施的状态。此外，他的导师的实验室有自己的4激光LSRII流式细胞仪和4柱Miltenyi磁性分离器。研究：TBI导致免疫抑制，使宿主易受继发感染。事实上，感染是TBI后死亡的主要原因。 初步数据表明，TBI导致先天免疫系统细胞的快速和持续损失以及向抗炎表型的转变。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TBI后感染性死亡率增加，从而启动TBI诱导的免疫功能障碍的发病机制。为了验证这一假设，我们建立了一个临床上适用的小鼠闭合性头部损伤模型，以特异性地询问周围神经元的功能。 对TBI的免疫反应我们的目的是确定单核细胞和巨噬细胞在TBI诱导的免疫抑制的发展中的作用，TBI是否驱动先天免疫应答朝向抗炎表型，以及单核细胞和巨噬细胞的耗竭是否降低TBI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由我们的模型诱导的免疫表型。此外，我们将采用一系列单核细胞/巨噬细胞耗竭实验，以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，以确定是否操纵单核细胞和巨噬细胞群体影响脑损伤动物继发性肺炎的易感性。最后，将评估单核细胞/巨噬细胞耗竭对TBI后皮质损失和神经元变性的影响。

 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.