Effect of pericyte stimulation on traumatic brain injury pathophysiology

周细胞刺激对创伤性脑损伤病理生理学的影响

• 批准号: 10361912
• 负责人: Corbin Bachmeier
• 金额: --
• 依托单位: BAY PINES VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10361912
• 关键词: Acute; Affect; Agonist; Alzheimer' s Disease; Animals; Appearance; Atrophic; Automobile Driving; Axon; Behavior; Biological; Blood Vessels; Brain; Brain Injuries; Cell Count; Cell Differentiation process; Cells; Cerebrum; Chronic; Chronic Phase; Cognitive; Craniocerebral Trauma; Deterioration; Disease; Disease Progression; Encephalitis; Functional disorder; Health; Homeostasis; Human; Impaired cognition; Individual; Inflammation; Inflammatory; Injury; Laminin; Ligands; Mediating; Mediator of activation protein; Modeling; Mus; Myelin; Neurodegenerative Disorders; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Pericytes; Phenotype; Phenytoin; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor B; Platelet-Derived Growth Factor beta Receptor; Population; Public Health; Reporting; Risk; Role; Signal Transduction; Specimen; Stimulus; Testing; Thinness; Time; Transgenic Organisms; Traumatic Brain Injury; Veterans; Work; combat; extracellular; fluid percussion injury; immunoregulation; improved; mild traumatic brain injury; military veteran; mouse model; neurobehavior; neuroinflammation; neurovascular unit; novel strategies; oligodendrocyte precursor; platelet-derived growth factor BB; precursor cell; prevent; receptor; remyelination; residence; response; tau Proteins; tau aggregation; tau mutation; treatment strategy; uptake; welfare; white matter; wound

Brain vascular pericytes are an essential component of the neurovascular unit and perform a number of diverse functions in regulating brain homeostasis. A common feature of many neurodegenerative disorders is a progressive disruption of vascular pericytes in the brain. The current studies observed pericyte degeneration in the brain at several time points following repetitive mild traumatic brain injury (r-mTBI) in mice. The influence of head trauma on the pericyte population may be the result of disruptions in the PDGF (platelet- derived growth factor) pathway. The interaction between the PDGF-BB ligand and the PDGFR-beta receptor is tightly regulated and required for pericyte function and survival. The current studies also found PDGF-BB levels in the brain were significantly diminished in r-mTBI mice and human TBI specimens. Thus, as pericyte health is highly dependent on stimulation of the PDGF pathway, the diminished availability of PDGF-BB in the brain following TBI may be driving pericyte degeneration post-injury. Moreover, given the role of pericytes in white matter homeostasis, extracellular tau disposition, and neuroinflammation, the deterioration of the pericyte population following head trauma could be a major driver of TBI pathophysiology. The hypothesis of this proposal is that stimulation of the PDGF pathway will improve pericyte function and mitigate the TBI phenotype. The objective of the proposed studies is to comprehensively evaluate the effect of PDGF-BB stimulation on TBI pathophysiology and cognitive dysfunction, as outlined in the following Aims, 1) investigate the effect of PDGF-BB on oligodendrocyte precursor cell (OPC) differentiation and remyelination following r- mTBI, 2) evaluate tau degradation and elimination in the r-mTBI brain upon PDGF-BB stimulation, 3) examine pericyte-mediated neuroinflammation in r-mTBI following PDGF-BB stimulation, and 4) determine the influence of chronic PDGF-BB stimulation on r-mTBI pathophysiology and cognitive behavior. To evaluate the effect of PDGF-BB stimulation in each of these Aims, the proposed studies will examine OPC differentiation in conditioned media from r-mTBI microvessels and assess remyelination in r-mTBI brains. For tau elimination, the tau degradation profile in isolated r-mTBI microvessels will be examined in addition to tau residence time in the brain of r-mTBI mice. For neuroinflammation, the proposed studies will identify the immunomodulatory factors secreted by r-mTBI pericytes, and the response of brain pericytes to TBI-relevant inflammatory stimuli. Lastly, the effect of a chronic PDGF-BB treatment paradigm on TBI pathophysiology and neurobehavior will be evaluated in r-mTBI animals. Collectively, this project will determine the contribution of brain pericyte degeneration to white matter deficits, tau accumulation, and neuroinflammation following head trauma. Moreover, the effect of PDGF-BB stimulation in mitigating these pathological features and cognitive dysfunction will be assessed following r-mTBI, which may provide a novel strategy for the treatment of brain injuries and potentially other neurodegenerative disorders.

脑血管周细胞是神经血管单位的重要组成部分， 调节大脑内环境稳定的功能。许多神经退行性疾病的一个共同特征是 大脑中血管周细胞的进行性破坏。目前的研究观察到周细胞变性， 在小鼠中重复性轻度创伤性脑损伤（r-mTBI）后的几个时间点的脑。的 头部创伤对周细胞群的影响可能是PDGF（血小板- 衍生生长因子）途径。PDGF-BB配体和PDGFR-β受体之间的相互作用是 周细胞功能和存活所需的严格调控。目前的研究还发现PDGF-BB 在r-mTBI小鼠和人TBI样本中脑中的水平显著降低。因此，作为周细胞 健康高度依赖于PDGF通路的刺激，在肿瘤中PDGF-BB的可用性降低， 脑外伤后的脑损伤可能导致损伤后周细胞变性。此外，鉴于周细胞在 白色物质稳态、细胞外tau蛋白沉积和神经炎症， 头部创伤后的周细胞群可能是TBI病理生理学的主要驱动因素。的假设 这一建议是PDGF通路的刺激将改善周细胞功能并减轻TBI 表型本研究的目的是全面评价PDGF-BB的作用 刺激对TBI病理生理学和认知功能障碍的影响，如以下目的所概述，1）研究 PDGF-BB对大鼠脑缺血再灌注后少突胶质前体细胞（OPC）分化和髓鞘再生的影响 mTBI，2）评估PDGF-BB刺激后r-mTBI脑中的tau降解和消除，3） 检查PDGF-BB刺激后r-mTBI中周细胞介导的神经炎症，以及4）确定 慢性PDGF-BB刺激对r-mTBI病理生理学和认知行为的影响。评价 PDGF-BB刺激在这些目的中的作用，拟议的研究将检查OPC分化 在来自r-mTBI微血管的条件培养基中，并评估r-mTBI脑中的髓鞘再生。对tau 除tau外，还将检查分离的r-mTBI微血管中的tau降解谱 在r-mTBI小鼠脑中的停留时间。对于神经炎症，拟议的研究将确定 r-mTBI周细胞分泌的免疫调节因子，以及脑周细胞对TBI相关免疫调节因子的反应。 炎症刺激。最后，慢性PDGF-BB治疗模式对TBI病理生理学的影响 并且将在r-mTBI动物中评价神经行为。总的来说，这个项目将决定 脑周细胞变性对白色物质缺陷、tau蛋白积聚和神经炎症的贡献 头部创伤后死亡此外，PDGF-BB刺激在减轻这些病理特征中的作用是显著的。 和认知功能障碍将在r-mTBI后进行评估，这可能为治疗脑外伤提供一种新的策略。 治疗脑损伤和潜在的其他神经退行性疾病。