Microglial process convergence following brain injury

脑损伤后小胶质细胞过程收敛

• 批准号: 10626687
• 负责人: Audrey D Lafrenaye
• 金额: $ 54.34万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10626687
• 关键词: 3-Dimensional; Acute; Address; Adult; Age; Agonist; Anti-Inflammatory Agents; Autopsy; Axon; Biological; Brain; Brain Injuries; Clinic; Clinical Trials; Coculture Techniques; Data; Diagnosis; Diffuse; Disease; Estrus; Family suidae; Female; Goals; Harvest; Healthcare; Hour; Human; Immune; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Influentials; Injury; Intervention; Investigation; Lead; Mammals; Mediating; Mediator of activation protein; Microglia; Microscopic; Modeling; Morbidity - disease rate; Mus; Neurites; Neuroimmune; Neurologic; Neurons; Pathologic; Pathology; Persons; Phenotype; Population; Preparation; Prevalence; Process; Proteins; RNA; Rattus; Rodent; Role; Sampling; Sex Differences; Signal Transduction; Stretching; Swelling; Synapses; TBI treatment; TNF gene; Thalamic structure; Therapeutic; Tissues; Translating; Traumatic Brain Injury; arm; axon injury; base; brain cell; brain tissue; central nervous system injury; cohort; cytokine; fluid percussion injury; human tissue; in vivo; inhibitor; male; metabolic rate; neuroinflammation; neurological pathology; neuronal survival; neuropathology; neurotoxic; novel; porcine model; reconstruction; repaired; response; sex; targeted treatment; treatment strategy

Project Abstract Traumatic brain injury (TBI) produces significant pathology, including post-injury inflammation (particularly within the thalamus), that can lead to long-term morbidities. Microglia, the innate immune cells of the brain, are critical mediators of neuroinflammation that can have either neurotoxic or neurotrophic effects. Progress has been made investigating TBI-induced neuroimmune responses in rodents and therapies showing great promise have moved to clinical trials but failed to translate into beneficial interventions for humans suffering TBI. However, therapies targeting processes that occur in higher order mammals, with immune responses, cytoarchitecture, and metabolic rates similar to humans, such as pigs, would be more likely to translate to the clinic successfully. The neuroinflammatory progression following brain injury in pigs, however, is not well- understood. Our preliminary data demonstrated that microglial processes converge onto injured axonal swellings (microglial process convergence; MPC) in the thalamus of micro pigs, that is not recapitulated in rats, following diffuse TBI but does appear to occur in humans. Studies in mice indicate that this microglial process convergence (MPC) requires functional P2Y12R, however, the mechanisms behind MPC in higher order mammals is currently unknown. Both our preliminary data and previous studies indicate that MPC may be an ameliorative process, promoting axonal outgrowth acutely post-injury. Therefore, the goal of this study is to assess the roles of microglial changes on pathological progression in a pig model of diffuse TBI. Studies indicate that males have greater pro-inflammatory responses and less axonal outgrowth compared to females. However, there are no known studies evaluating sex as a biological variable in MPC. Accordingly, the current study will address the following specific aims 1) to evaluate the effects of inflammatory and P2Y12R modulation on MPC, neuronal survival and axonal outgrowth/retraction following injury and 2) to assess the prevalence of MPC in human brain tissue following diffuse TBI and other CNS injuries/diseases. To address these aims we will complete quantitative 3D assessments of multiplexed immunohistological samples for microglial-axonal interactions in vitro and in pigs to determine the degree of MPC in relation to axonal outgrowth/retraction changes, P2Y12R expression, and sex-related variability. As the prevalence of MPC following brain injury in the human population is currently unknown, we will also probe for the degree of MPC onto injured axonal swellings, neuronal survival, axonal outgrowth/retraction, and spatially resolved RNA profiles in a unique cohort of postmortem brain tissue. This study is significant because understanding microglial-neuronal interactions and repair mechanisms in higher order species and humans of both sexes will translate into therapeutics strategies for the treatment of TBI.

项目摘要 创伤性脑损伤 (TBI) 会产生显着的病理变化，包括损伤后炎症（特别是 丘脑内），这可能导致长期发病。小胶质细胞是大脑的先天免疫细胞， 神经炎症的关键介质，可能具有神经毒性或神经营养作用。进展有 研究了啮齿动物中 TBI 诱导的神经免疫反应和治疗方法，显示出良好的效果 承诺已进入临床试验，但未能转化为对遭受苦难的人类有益的干预措施 创伤性脑损伤。然而，针对高等哺乳动物中发生的具有免疫反应的过程的疗法， 与人类（例如猪）相似的细胞结构和代谢率更有可能转化为 诊所成功。然而，猪脑损伤后的神经炎症进展情况并不理想。 明白了。我们的初步数据表明，小胶质细胞过程汇聚到受伤的轴突上 微型猪丘脑的肿胀（小胶质细胞过程收敛；MPC），在大鼠中没有重现， 继弥漫性 TBI 后发生，但似乎确实发生在人类身上。对小鼠的研究表明，这种小胶质细胞过程 收敛（MPC）需要功能性的 P2Y12R，然而，MPC 背后的机制是高阶的 哺乳动物目前未知。我们的初步数据和之前的研究都表明 MPC 可能是一种 改善过程，促进损伤后急性轴突生长。因此，本研究的目标是 评估小胶质细胞变化对弥漫性 TBI 猪模型病理进展的作用。 研究表明，与男性相比，男性具有更强的促炎症反应和更少的轴突生长 女性。然而，目前还没有研究将性别作为 MPC 的生物学变量进行评估。据此， 当前的研究将解决以下具体目标 1) 评估炎症和 P2Y12R 对 MPC、损伤后神经元存活和轴突生长/回缩的调节以及 2) 评估弥漫性 TBI 和其他 CNS 后人脑组织中 MPC 的患病率 受伤/疾病。为了实现这些目标，我们将完成多路复用的定量 3D 评估 体外和猪体内小胶质细胞-轴突相互作用的免疫组织学样本，以确定相互作用的程度 MPC 与轴突生长/回缩变化、P2Y12R 表达和性别相关变异相关。作为 目前尚不清楚人群中脑损伤后 MPC 的患病率，我们还将探讨 MPC 对受损轴突肿胀、神经元存活、轴突生长/回缩以及空间的程度 解析了一组独特的死后脑组织中的 RNA 谱。这项研究意义重大，因为 了解高阶物种和人类的小胶质细胞-神经元相互作用和修复机制 两种性别都将转化为治疗 TBI 的治疗策略。