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.

项目概要创伤性脑损伤 (TBI) 每年影响数百万人，导致神经元回路中断，持续的神经功能缺陷，以及继发感染的易感性增加。 TBI 后，外周免疫系统 (PIS) 细胞会导致随后的神经炎症并加剧神经病理学通过归巢到受伤的大脑，与微病理特征相关联，并释放炎症因子。此外，创伤性脑损伤后，受伤的大脑会向血液中释放损伤信号，改变 PIS 稳态和功能。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、神经系统结果受损以及死亡率。然而，这两个器官系统如何相互影响的机制和结果从未在临床相关的弥漫性 TBI 模型中研究过创伤。因此，我建议量化 TBI 后大脑中浸润的 PIS 的石灰、范围和位置，以研究 TBI 引起的变化基线时和临床相关免疫挑战后的 PIS 功能，并制造治疗药物治疗策略将利用 PIS 细胞来调节 TBI 诱导的神经炎症。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 TBI 后将静脉注射载有微粒的细胞。此后的治疗效果这些细胞将通过表征渗透程度、对 PIS 的影响以及分布进行量化神经病理学。为了完成这项工作，我建议利用高保真闭头猪模型弥漫性 TBI——这是当今使用的与临床最相关的 TBI 生物力学模型——以及全面、定量的 PIS 表征。我假设浸润的免疫细胞将定位于微病理学特征，先天性和适应性 PIS 将在 TBI 后表现出慢性免疫抑制，并且当浸润的免疫细胞负载免疫调节剂时，神经炎症将会减轻微粒子。从该提案中获得的信息将制定一种与翻译相关的治疗策略 TBI 可以改善受影响个体的护理并为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 VA Medical 完成中心拥有其他地方所没有的独特的资源、设备和制度环境世界上其他地方。在这次职业发展奖期间，我将获得诱导伤害装置猪闭头弥漫性 TBI、用于全面 PIS 表征的设备和测定法，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，开发转化免疫调节工具，并培养坚定的指导，以培养神经免疫相互作用的专门研究领域这将使我能够转变为一名独立研究员。