Understanding and Controlling Neuro-immune Interactions Following Traumatic Brain Injury

项目总结 创伤性脑损伤(TBI)每年影响数百万人，导致神经元电路中断， 持续的神经缺陷，增加了对二次感染的易感性。在TBI之后， 外周免疫系统(PIS)细胞有助于随后的神经炎症并加剧 归巢于损伤的大脑，结合微病理特征，并释放的神经病理学 炎症因子。此外，在脑外伤后，受伤的大脑向血液释放损伤信号， 改变PIS动态平衡和功能。事实上，对PIS的这些调整可能会导致慢性 免疫缺陷，组织再生能力降低，神经预后受损，以及 死亡率。然而，这两个器官系统如何相互影响的机制和结果 在弥漫性脑损伤的临床相关模型中，创伤从未被研究过。因此，我建议量化 颅脑损伤后脑内浸润性PIS的分布、范围和位置，以探讨脑损伤后脑内PIS的变化 在基线和临床相关免疫挑战后的PIS功能，并制作一种治疗性 治疗策略将使用PIS的细胞来调节脑损伤引起的神经炎症。具体来说， 免疫调节微粒将被加载到渗透的免疫细胞中，这些自体 微颗粒负载细胞将在颅脑损伤后静脉注射。此后，该药的治疗效果 这些细胞将通过表征渗透的程度、对PIS的影响以及 神经病理学。为了完成这项工作，我建议使用一种高保真的闭合头猪临床前模型 弥漫性脑损伤-这是目前使用的最具临床相关性的脑损伤生物力学模型-以及 全面和定量的PIS表征。我假设渗入的免疫细胞将定位于 微病理特征，脑外伤后先天的和适应性的PIS将表现出慢性免疫抑制，并且 当渗入的免疫细胞负载免疫调节剂时，神经炎症将得到缓解 微粒。从这项提案中获得的信息将制定与翻译相关的治疗策略 TBI可以改善对受影响个人的护理，并向有关神经免疫的基础科学问题提供信息 互动。重要的是，这项研究只能在宾夕法尼亚大学和退伍军人管理局完成 中心拥有独特的资源、设备和制度环境，这是任何地方都无法获得的 在世界上的其他地方。在这个职业发展奖期间，我将有机会接触到导致 猪闭头弥漫性脑损伤，用于综合PIS表征的设备和检测， 免疫调节微粒的制造，以及大型动物设施。这一职业发展奖将提供 一个独特的培训机会，回答基本的科学问题，开发翻译免疫调节工具， 培养忠诚的导师关系，这将培养神经免疫相互作用的专门研究利基 这将使我能够过渡到一名独立的研究员。

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.