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

白质损伤越来越被认为是创伤性脑损伤（TBI）的一个关键标志，这种类型的损伤尤其与不良的临床结果相关1。对脑外伤患者的尸检研究表明，脑外伤后少突胶质细胞明显死亡，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损失无疑会导致神经外伤后的死亡和残疾，但髓鞘细胞、少突胶质细胞的损失以及存活轴突髓鞘修复失败已被证明与TBI后的神经残疾相关（2,3）。最近，HMGB1 （High-mobility group box 1 protein）被发现是脑外伤后脑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来保护和修复脑外伤后白质的有吸引力的靶点（1,3）。我们最近发现HMGB1是大鼠损伤后神经元存活和少突胶质细胞增殖和分化的关键神经炎症介质。这些观察结果是相关的，因为脑外伤后白质和髓鞘形成的丧失可以解释为：a)脑外伤后少突胶质细胞直接死亡，和/或b)神经外伤后少突胶质祖细胞增殖或成熟受损，(4)导致存活的轴突缺乏有意义的髓鞘形成。少突胶质细胞本身对有害刺激非常敏感(2)，保护和支持其祖细胞已成为支持中枢神经系统损伤后髓鞘再生的一种有吸引力的策略(4)。在这个提议中，我们打算在一个落锤重的3D人类皮层细胞培养模型中验证这些发现。这种新颖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，这在现有文献中尚未被研究，并测试这些反应如何通过hmgb1介导的信号传导的免疫调节来操纵，和/或其他相关的损伤相关分子模式（DAMP）介导的途径。这可能会导致识别新的途径，这些途径可能适用于药理学调节，以改善TBI患者的预后。几种作用于hmgb1信号轴的药理学药物已经在其他神经病理患者队列中投入临床使用/正在进行2-3期试验，因此，如果该途径在本研究中被确定为脑外伤后白质损伤和修复的潜在调节剂，则有可能快速临床转化。提议的学生在TBI的人体组织模型中评估这些途径是该提案的一个新组成部分，尚未在现有文献中进行评估。1.帕克等人。危险区域：HMGB1危险信号在创伤性脑损伤中的作用的系统综述。脑损伤杂志，31 -8,（2017）邓特等人。成年小鼠外伤性脑损伤后少突胶质细胞的出生和死亡。PLoS One 10 （2015）Armstrong等人。髓磷脂和少突胶质细胞系细胞在创伤性脑损伤后白质病理和可塑性中的作用。中国生物医学工程学报（英文版）。Veronique等人。少突胶质系的细胞，髓鞘形成和再髓鞘形成。5.生物化学与生物物理学报，2002,18(4):481 - 481（2011）。Marmarou et al.（编）急性神经损伤的动物模型。施普林格协议手册。胡玛纳出版社。(2009)

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)