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

• 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
• 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

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）每年影响数百万人，导致神经元回路中断， 持续的神经功能缺损和继发感染的易感性增加。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 神经病理学通过归巢到受伤的大脑，与显微病理学特征相关联，并释放 炎症因子此外，在TBI之后，受伤的大脑将损伤信号释放到血液中， 改变PIS的稳态和功能。事实上，对PIS的这些调整可能导致慢性 免疫缺陷，组织再生能力降低，神经系统结果受损， 死亡率然而，这两个器官系统如何相互影响的机制和结果， 创伤从未在弥漫性TBI的临床相关模型中进行过研究。因此，我建议量化 TBI后脑内浸润性PIS的时间、范围和位置，以研究TBI诱导的变化， 在基线时和临床相关免疫激发后的PIS功能，并制备治疗性药物组合物。 治疗策略，将采用PIS的细胞来调节TBI诱导的神经炎症。具体地说， 免疫调节微粒将被装载到浸润的免疫细胞中， 将在TBI后静脉内施用负载微粒的细胞。此后， 这些细胞将通过表征浸润的程度、对PIS的影响以及 神经病理学为了完成这项工作，我建议利用一个高保真的临床前猪模型的封闭头， 弥漫性TBI -这是目前使用的TBI生物力学的最临床相关模型-沿着 全面和定量的PIS表征。我假设浸润的免疫细胞会定位于 在TBI后，先天性和适应性PIS将表现出慢性免疫抑制， 当浸润的免疫细胞负载免疫调节剂时， 微粒。从该提案中获得的信息将制定一项预防性相关的治疗策略， TBI可以改善对受影响个体的护理，并告知有关神经免疫的基础科学问题 交互.重要的是，这项研究只能在宾夕法尼亚大学和VA Medical完成。 中心因其独特的资源、设备和制度环境而在任何地方都不具备 世界上的其他地方。在这个职业发展奖，我将有机会获得伤害装置，诱导 猪闭头弥漫性TBI，用于全面PIS表征的设备和测定， 免疫调节微粒制造和大型动物设施。这个职业发展奖将提供 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， 并培养致力于指导，这将培养一个专门的研究利基神经免疫相互作用 这将使我成为一名独立的研究人员。