Pain after Trauma and TBI: Epigenetic Mechanisms

 说明： 在平民环境中遭受创伤后，与战争有关的伤害后的慢性疼痛和残疾 而手术后的情况出人意料地普遍。与创伤性脑损伤(TBI)合并外周损伤相关的慢性疼痛问题尤其严重，我们还没有得到充分验证的治疗方法。不幸的是，受伤后的慢性疼痛也会导致残疾和认知障碍。为了帮助解释这个问题，在人类和动物身上的观察表明，中枢下行去甲肾上腺素能回路和传入神经通路汇聚在脊髓的背角，以调节特定神经元群体中持续的神经可塑性变化。此外，表观遗传机制已经作为一组过程出现，能够将这些内在因素(例如下行疼痛调制)和后天因素(例如来自组织破坏的神经输入)整合到细胞功能的持续变化中。这种过程是由创伤性脑损伤和痛苦的伤害所激活的。神经可塑性相关的神经营养因子脑源性神经营养因子(BDNF)是脊髓表观遗传调控的痛敏化的关键部分。因此，本项目的主要目标是明确表观遗传机制及其靶基因在支持周围损伤后疼痛和相关变化中的作用，特别是在脑外伤的背景下。在第一个目标中，我们在啮齿动物模型中评估组织乙酰转移酶(HAT)抑制剂可以减少软组织损伤(切口)、脑外伤后的疼痛、残疾和认知功能障碍的假说。将使用一组全面的结果测量方法，重点放在痛觉、自发疼痛、功能(步态)异常和认知(记忆)变化上。药理学治疗将包括高度选择性的药物和适合翻译使用的药物。在第二个目的中，我们评估了HAT抑制剂阻断组蛋白乙酰化以及周围损伤、脑外伤和这些损伤联合后脊髓疼痛相关趋化因子信号分子表达增强的假说。在这一目标中，我们将重点放在一个关键的疼痛相关基因的调控上，BDNF是已知的表观遗传调控基因。通过组蛋白乙酰化对该分子表达的调节以及BDNF在疼痛和功能结果中的直接作用将被确定。在第三个也是最后一个目标中，我们将评估通过α-2肾上腺素能受体起作用的去甲肾上腺素能下行抑制变化的作用，作为将脑外伤与正在研究的脊髓神经可塑性变化联系起来的途径。同样，在整个目标过程中将使用适合于人类使用的选择性药物。在项目完成时，我们希望更好地了解创伤性脑损伤、周围损伤和复合损伤是如何导致慢性疼痛的。在这项评估的过程中，我们将描述特定的表观遗传机制、基因靶点和下行调控通路在这种非常有问题的慢性疼痛中的作用。我们期待着能够计划翻译人类研究。

 DESCRIPTION: Chronic pain and disability after war-related injuries, after trauma sustained in civilian settings and after surgery is unexpectedly common. Chronic pain related to traumatic brain injury (TBI) in combination with peripheral injuries is particularly problematic, and we have no well-validated treatments. Unfortunately, chronic pain after injuries also supports disability and cognitive impairment. Helping to explain this problem, observations in humans and animals suggest that central descending noradrenergic circuits and afferent neural pathways converge on the dorsal horn of the spinal cord to modulate sustained neuroplastic changes within specific populations of neurons. Furthermore, epigenetic mechanisms have emerged as a group of processes capable of integrating these intrinsic (e.g. descending pain modulation) and acquired (e.g. neural input from tissue disruption) factors into persistent changes in cellular functions. Such processes are activated by TBI and painful injuries. The neuroplasticity-related neurotrophin brain derived neurotrophic factor (BDNF) is a key part of spinal epigenetically-regulated pain sensitization. The main objective of this project is, therefore, to define the role of epigenetic mechanisms and their target genes in supporting pain and related changes after peripheral injury, particularly in the setting of TBI. In the first aim we evaluate the hypothesis that histoe acetyl transferase (HAT) inhibitors reduce pain, disability and cognitive dysfunction after soft tissue injury (incision), TBI and the combination of these injuries in a rodent model. A comprehensive group of outcome measures focused on nociception, spontaneous pain, functional (gait) abnormalities and cognitive (memory) changes will be used. Pharmacological treatments will include highly selective agents and drugs suitable for translational use. In the second aim we evaluate the hypothesis that HAT inhibitors block histone acetylation and the enhanced spinal expression of pain-related chemokine signaling molecules after peripheral injury, TBI and the combination of these injuries. We focus in this aim on the regulation of a key pain-related genes known to be epigenetically regulated, BDNF. The regulation of expression of this molecule through histone acetylation and the direct role of BDNF in pain and functional outcomes will be determined. In the third and final aim we will evaluate the role of changes in descending noradrenergic inhibition acting through the alpha-2 adrenergic receptor as a pathway linking TBI to the spinal neuroplastic changes under study. Again, selective agents suitable for use in humans will be used throughout this aim. At the time of completion of the project we expect to understand better how TBI, peripheral injury and the combination of injuries cause chronic pain. In the process of this evaluation we will delineate the roles of specific epigenetic mechanisms, gene targets and descending regulatory pathways in contributing to this very problematic form of chronic pain. We anticipate being in position to plan translational human studies.