The roles of the alarmin HMGB1 in injury and repair of white matter after traumatic brain injury

脑白质损伤越来越被认为是创伤性脑损伤(TBI)的一个重要标志，这种类型的损伤尤其与不良的临床结果有关。对脑外伤患者的尸检研究表明，脑损伤后少突胶质细胞显著死亡，白质完整性与中枢神经系统损伤后的运动和心理恢复有关(1，2)。虽然神经元损伤和轴突丢失无疑是神经创伤后死亡和残疾的因素，但髓鞘细胞、少突胶质细胞的丢失和幸存轴突的髓鞘修复失败已被证明与脑外伤后的神经残疾有关(2，3)。最近，HMGB1(高迁移率组盒1蛋白)已成为脑创伤后脑部炎症的关键启动因子(1)。因此，HMGB1介导的通路是开发新的治疗方法以保护和修复脑创伤后脑白质的有吸引力的靶点(1，3)。我们最近发现HMGB1是一种关键的神经炎性介质，可以减少大鼠损伤后神经元的存活和少突胶质细胞的增殖和分化。这些观察是相关的，因为脑损伤后白质的丢失和髓鞘形成可能是由a)脑损伤后少突胶质细胞直接死亡，和/或b)神经创伤后少突胶质前体细胞的增殖或成熟受损，(4)导致存活轴突缺乏有意义的再髓鞘形成所致。少突胶质细胞本身对伤害性刺激非常敏感(2)，保护和支持其祖细胞已成为支持中枢神经系统损伤后重新髓鞘形成的一种有吸引力的策略(4)。在这项建议中，我们打算在减重的3D人类皮质细胞培养模型中验证这些发现。这种新的实验方法将使我们能够探索神经创伤对人类少突胶质细胞的影响，这在现有的文献中还没有被研究，并测试如何通过免疫调节HMGB1介导的信号和/或其他相关的损伤相关分子模式(DAMP)介导的通路来操纵这些反应。这可能导致识别新的通路，这些通路可能服从于药物调节来改善脑外伤患者的预后。作用于HMGB1信号轴的几种药物已经在临床使用，并在其他神经病理患者队列中进行2-3期试验，因此，如果这一途径被确定为脑外伤后脑白质损伤和修复的潜在调节器，则有可能快速临床转化。拟议的学生身份在脑外伤的人体组织模型中对这些通路的评估是该提议的一个新组成部分，现有文献尚未对其进行评估。1.Parker等人。危险区域：系统回顾HMGB1危险信号在创伤性脑损伤中的作用。Brain Inj 31，2-8，(2017)2.登特等人。成年小鼠脑创伤后少突胶质细胞的出生和死亡。PLOS One 10(2015)3.阿姆斯特朗等人。脑外伤后白质病理和可塑性中的髓鞘和少突胶质细胞谱系细胞。神经药理学。110：654-659(2016)4.Veronique等人。少突胶质细胞谱系、髓鞘形成和再髓鞘形成。《Biochimica et BiPhysica Acta(BBA)--疾病的分子基础》，1812,184-193(2011)5.Marmarou等。(EDS)急性神经损伤的动物模型。斯普林格协议手册。胡马纳出版社。(2009年)

White matter injury is increasingly recognised as a key hallmark of traumatic brain injury (TBI), this type of injury is particularly associated with poor clinical outcome1. Autopsy studies of TBI victims demonstrate significant oligodendrocyte cell death post TBI, and white matter integrity is linked to both motor and psychological recovery after injury to the central nervous system (1,2). Whilst neurone injury and axonal loss are undoubtedly contributary to death and disability post-neurotrauma, loss of myelinating cells, oligodendrocytes, and failure of repair of myelination of surviving axons has been demonstrated to correlate with neurological disability after TBI (2,3). Recently, HMGB1 (High-mobility group box 1 protein), has emerged as a key initiator of brain inflammation after TBI (1). HMGB1-mediated pathways are thus attractive targets for the development of novel therapeutic approaches to protect and repair white matter after brain trauma (1,3). We have recently identified HMGB1 as a key neuroinflammatory mediator that decreased neuronal survival and oligodendroglial cell proliferation and differentiation after injury in rats. These observations are relevant as the loss of white matter and myelination after TBI may be explained by a) direct oligodendrocyte death after TBI, and/or b) impaired proliferation or maturation of oligodendroglial progenitors following neurotrauma, (4) leading to a lack of meaningful remyelination of surviving axons. Oligodendrocytes themselves are exquisitely sensitive to noxious stimuli, (2) and protection and support of their progenitors has emerged as an attractive strategy to support remyelination following injury to the central nervous system (4). In this proposal we intend to validate these findings in a drop-weight 3D human cortical cell culture model. This novel experimental approach will allow us to probe the impacts of neurotrauma upon human oligodendroglial cells, which is yet to be investigated in the existing literature, and test how these responses might be manipulated through immunomodulation of HMGB1-mediated signalling, and/or other related damage-associated-molecular-pattern (DAMP) mediated pathways. This may lead to the identification of novel pathways which may be amenable to pharmacological modulation to improve outcomes for TBI patients. Several pharmacological agents acting upon the HMGB1-signalled axis are already in clinical use/undergoing phase 2-3 trials in other neuropathological patient cohorts, and so if this pathway is identified as a potential modulator of white matter injury and repair after TBI in this fellowship, there is the potential for rapid clinical translation. The proposed studentship's assessment of these pathways in a human tissue models of TBI is a novel component of the proposal which is yet to assessed in the existing literature. 1.Parker et al. The danger zone: Systematic review of the role of HMGB1 danger signalling in traumatic brain injury. Brain Inj 31, 2-8, (2017)2. Dent et al. Oligodendrocyte birth and death following traumatic brain injury in adult mice. PLoS One 10 (2015)3. Armstrong et al. Myelin and oligodendrocyte lineage cells in white matter pathology and plasticity after traumatic brain injury. Neuropharmacology. 110: 654-659 (2016)4. Veronique et al. Cells of the oligodendroglial lineage, myelination, and remyelination. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1812, 184-193 (2011)5. Marmarou et al. (eds) Animal Models of Acute Neurological Injuries. Springer Protocols Handbooks. Humana Press. (2009)