Microglial process convergence following brain injury

脑损伤后小胶质细胞过程收敛

• 批准号: 10657968
• 负责人: Audrey D Lafrenaye
• 金额: $ 54.09万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657968
• 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; Mammals; Mediating; Mediator; Microglia; Microscopic; Modeling; Morbidity - disease rate; Mus; Nervous System Trauma; Neurites; Neuroimmune; Neurologic; Neurons; Pathologic; Pathology; Persons; Phenotype; Population; Preparation; Prevalence; Process; Proteins; RNA; Rattus; Rodent; Role; Sampling; Sex Differences; Signal Transduction; Stretching; Swelling; TBI treatment; TNF gene; Thalamic structure; Therapeutic; Tissues; Traction; Translating; Traumatic Brain Injury; arm; axon injury; brain cell; brain tissue; central nervous system injury; cohort; cytokine; fluid percussion injury; glial activation; human tissue; in vivo; inhibitor; male; metabolic rate; neuroinflammation; neurological pathology; neuronal survival; neuropathology; neurotoxic; novel; porcine model; postsynaptic; 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）会产生重要的病理学，包括伤害后炎症（特别是 在丘脑中），这可能导致长期病毒。小胶质细胞是大脑的先天免疫细胞，是 神经炎症的关键介体可以具有神经毒性或神经营养作用。进度有 已经研究了啮齿动物和疗法中TBI诱导的神经免疫反应的表现出色 承诺已进入临床试验，但未能转化为对苦难的人类的有益干预措施 TBI。但是，针对高阶哺乳动物的靶向过程，免疫反应， 细胞结构和类似于人类（例如猪）的代谢率更可能转化为 诊所成功。然而，猪脑损伤后的神经炎症进展不是很好 理解。我们的初步数据表明，小胶质细胞过程会收敛到受伤的轴突上 微猪丘脑中的肿胀（小胶质过程收敛; MPC），在大鼠中未概括， 按照弥漫性TBI，但似乎确实发生在人类中。小鼠的研究表明这种小胶质过程 但是，收敛（MPC）需要功能性P2Y12R，但是，MPC背后的机制高阶 哺乳动物目前未知。我们的初步数据和以前的研究都表明MPC可能是 改善过程，促进轴突生长急性后伤口。因此，这项研究的目的是 评估小胶质变化在弥漫性TBI模型中病理进程的作用。 研究表明，与男性相比，男性具有更大的促炎反应和轴突生长的较少 女性。但是，尚无已知的研究将性别评估为MPC中的生物变量。因此， 当前的研究将解决以下特定目的1）评估炎症和 损伤后的MPC，神经元存活和轴突生长/回收的P2Y12R调制和2） 评估弥漫性TBI和其他CNS后人脑组织中MPC的患病率 伤害/疾病。为了解决这些目标，我们将完成多路复用的定量3D评估 在体外和猪中用于小胶质细胞 - 轴相互作用的免疫组织学样本，以确定 MPC与轴突产物/缩回变化，P2Y12R表达和与性别相关的变异性有关。作为 目前，人口脑损伤后MPC的患病率目前尚不清楚，我们还将探测 MPC在受伤的轴突肿胀，神经元存活，轴突生长/缩回和空间上的程度 在独特的尸体后脑组织中解析了RNA谱。这项研究很重要，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 两性都将转化为治疗TBI的治疗策略。