Effect of pericyte stimulation on traumatic brain injury pathophysiology

脑血管周细胞是神经血管单位的重要组成部分，具有多种不同的功能 调节大脑动态平衡的功能。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。 小鼠反复轻度创伤性脑损伤(r-mTBI)后不同时间点的脑组织变化。这个 头部创伤对周细胞数量的影响可能是由于PDGF(血小板-血小板)的破坏所致。 衍生生长因子)途径。PDGF-BB配体与PDGFR-β受体的相互作用是 受到严格的调控，是周细胞功能和生存所必需的。目前的研究还发现PDGF-BB 在r-mTBI小鼠和人脑损伤标本中，大脑中的水平显著降低。因此，作为周细胞 健康高度依赖于PDGF途径的刺激，PDGF-BB在 颅脑损伤后的脑损伤可能是导致伤后周细胞变性的原因之一。此外，鉴于周细胞在细胞周期中的作用 白质稳态、细胞外tau处置和神经炎症、 颅脑创伤后的周细胞群可能是脑外伤病理生理学的主要驱动因素。的假说 这表明刺激PDGF途径将改善周细胞功能，减轻脑损伤。 表型。建议研究的目的是综合评价PDGF-BB的作用 刺激对颅脑损伤的病理生理和认知功能障碍，如以下目标所述，1)调查 PDGF-BB对少突胶质前体细胞分化及再髓鞘形成的影响 MTBI，2)评估PDGF-BB刺激下r-mTBI脑内tau的降解和消除，3) 检测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病理生理和认知行为的影响。评估 PDGF-BB刺激在这些目的中的作用，拟议的研究将检查OPC的分化 在r-mTBI微血管的条件培养液中，评估r-mTBI脑中的重新髓鞘形成。对于tau 除tau外，还将检测分离的r-mTBI微血管中tau的降解情况。 R-mTBI小鼠在脑内的停留时间。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及脑周细胞对脑损伤相关反应的研究 炎性刺激。最后，慢性PDGF-BB治疗模式对脑外伤病理生理学的影响 神经行为将在r-mTBI动物身上进行评估。总体而言，这个项目将决定 脑周细胞变性对脑白质缺陷、tau蓄积和神经炎症的作用 在头部创伤之后。此外，PDGF-BB刺激在减轻这些病理特征方面的作用 认知功能障碍将在r-mTBI后进行评估，这可能为 治疗脑损伤和潜在的其他神经退行性疾病。

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.