Understanding and Controlling Neuro-immune Interactions Following Traumatic Brain Injury

了解和控制创伤性脑损伤后的神经免疫相互作用

基本信息

批准号：
10686307
负责人：
Kathryn Leigh Wofford
金额：
$ 10.99万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686307
关键词：
3-Dimensional Acceleration Affect Animal Model Animals Anti-Inflammatory Agents Autologous Axon Basic Science Behavior Behavioral Biological Assay Biomechanics Blood Blood - brain barrier anatomy Brain Brain Injuries Caring Cell Separation Cells Cessation of life Chronic Clinical Pathology Cytoskeleton Devices Diffuse Environment Equipment Exhibits Family suidae Female Flow Cytometry Fostering Gene Expression Head Health Home Homeostasis Homing Immune Immune response Immune system Immunohistochemistry Immunologic Deficiency Syndromes Immunology Immunosuppression Impairment In Vitro Individual Infection Infiltration Inflammatory Injury Institution K-Series Research Career Programs Laboratories Laboratory Research Limes Location Macrophage Medical center Mentors Mentorship Modeling Myelin National Institute of Neurological Disorders and Stroke Nerve Regeneration Nervous System Nervous System Trauma Neuroimmune Neurologic Deficit Neurological outcome Neurons Organ Size Outcome Pathologic Pennsylvania Peripheral Persons Phagocytosis Phenotype Predisposition Production Protein Secretion Reactive Oxygen Species Regenerative capacity Research Research Personnel Resources Secondary to Signal Transduction Site Testing Therapeutic Time Tissues Training Trauma Traumatic Brain Injury Treatment Efficacy Universities Vascular blood supply Whole Blood Work animal facility body system career career development clinically relevant cytokine design fabrication immune activation immune cell infiltrate immunoengineering immunomodulatory strategy immunoregulation improved in vitro Assay in vivo innovation intravenous administration lymphoid organ male minimally invasive monocyte mortality neuroimmunology neuroinflammation neuronal circuitry neuronal survival neuropathology neurophysiology neuroprotection new technology novel particle peripheral blood porcine model pre-clinical regenerative tissue secondary infection tissue processing tissue regeneration tool training opportunity translational approach treatment strategy

项目摘要

PROJECT SUMMARY Traumatic brain injury (TBI) affects millions of individuals annually resulting in disrupted neuronal circuitry, persistent neurological deficits, and increased susceptibility to secondary infections. Following TBI, the peripheral immune system (PIS) cells contribute to subsequent neuroinflammation and exacerbate neuropathology by homing to the injured brain, associating with micropathological features, and releasing inflammatory factors. Additionally, following TBI, the injured brain releases damage signals into the blood which alters PIS homeostasis and functionality. Indeed, these adjustments to the PIS can result in chronic immunodeficiency, reduced tissue regenerative capacity, impaired neurological outcomes, and an increased mortality rate. However, the mechanisms and outcomes of how these two organ systems affect one another after trauma has never been investigated in a clinically relevant model of diffuse TBI. Therefore, I propose to quantify the liming, extent, and location of the infiltrating PIS in the brain after TBI, to investigate TBI-induced changes to PIS functionality at baseline and after a clinically relevant immune challenge, and to fabricate a therapeutic treatment strategy that will employ cells of the PIS to modulate TBI-induced neuroinflammation. Specifically, immunomodulatory microparticles will be loaded into infiltrating immune cells and these autologous microparticle-loaded cells will be administered intravenously after TBI. Thereafter, the therapeutic efficacy of these cells will be quantified by characterizing the extent of infiltration, effects on the PIS, and distribution of neuropathology. To complete this work, I propose to utilize a high-fidelity preclinical porcine model of closed-head diffuse TBI - which is the most clinically relevant model of TBI biomechanics in use today - along with comprehensive and quantitative PIS characterization. I hypothesize that infiltrating immune cells will localize with micropathological features, the innate and adaptive PIS will exhibit chronic immunosuppression after TBI, and that neuroinflammation will be mitigated when infiltrating immune cells are loaded with immunomodulatory microparticles. Information gained from this proposal will develop a translationally-relevant treatment strategy for TBI that could improve care of affected individuals and inform basic science questions about neuro-immune interactions. Importantly, this research can only be completed at the University of Pennsylvania and VA Medical Center because of unique resources, equipment, and institutional environment that is not available anywhere else in the world. During this career development award, I will have access the injury device that induces the porcine closed-head diffuse TBI, equipment and assays for comprehensive PIS characterization, immunomodulatory microparticle fabrication, and large animal facilities. This career development award will offer a unique training opportunity, answer basic scientific questions, develop translational immunomodulatory tools, and foster committed mentorship that will cultivate a specialized research niche on neuro-immune interactions that will allow me to transition into an independent researcher.

项目摘要创伤性脑损伤（TBI）每年影响数百万个个体，导致神经元电路中断，持续的神经系统缺陷，并增加对继发感染的敏感性。遵循TBI，外周免疫系统（PIS）细胞有助于随后的神经炎症和恶化神经病理学通过将受伤的大脑寄养，与微病理特征相关联，并释放炎症因素。此外，在TBI之后，受伤的大脑将损害信号释放到血液中改变PIS稳态和功能。确实，这些对PI的调整可能会导致慢性免疫缺陷，组织降低的再生能力，神经系统损害以及增加死亡率。但是，这两个器官系统如何相互影响的机制和结果从未在弥漫性TBI的临床相关模型中研究创伤。因此，我建议量化 TBI后，大脑中浸润性PI的限制，程度和位置，以研究TBI诱导的变化基线和临床相关的免疫挑战后的PIS功能，并制造治疗性将使用PI细胞调节TBI诱导神经炎症的治疗策略。具体来说，免疫调节微粒将被加载到浸润的免疫细胞中，这些自体细胞将 TBI后将静脉内静脉内给予微粒的细胞。此后，这些细胞将通过表征浸润程度，对PI的影响以及分布来量化这些细胞神经病理学。为了完成这项工作，我建议使用闭合头的高保真临床前猪模型弥漫性TBI-这是当今使用的TBI生物力学最相关的模型 - 全面和定量的PIS表征。我假设浸润的免疫细胞将与微病理特征，先天和适应性PI将在TBI后表现出慢性免疫抑制，并且当浸润免疫细胞加载免疫调节时，这种神经炎症将得到缓解微粒。从该提案中获得的信息将制定与翻译相关的治疗策略可以改善受影响个人的护理并为基础科学提供有关神经免疫的问题的TBI 互动。重要的是，这项研究只能在宾夕法尼亚大学和VA Medical完成由于独特的资源，设备和机构环境而居中世界上的其他。在这个职业发展奖中，我将获得诱发的伤害设备猪闭合漫射TBI，设备和测定法，用于全面的PIS表征，免疫调节微粒制造和大型动物设施。该职业发展奖将提供独特的培训机会，回答基本科学问题，开发翻译免疫调节工具，和养育指导的指导，该指导将培养有关神经免疫相互作用的专业研究。这将使我能够过渡到独立的研究人员。