Pain after Trauma and TBI: Epigenetic Mechanisms

创伤和创伤性脑损伤后的疼痛：表观遗传机制

• 批准号: 9076504
• 负责人: DAVID J. CLARK
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076504
• 关键词: Acetylation; Address; Affect; Afferent Pathways; Animal Model; Animals; Behavioral Assay; Biological Models; Brain-Derived Neurotrophic Factor; Cell physiology; Clinical; Cognitive; Cognitive deficits; Connective Tissue; Curcumin; Epigenetic Process; Evaluation; Gait abnormality; Gene Targeting; General Population; Genes; Goals; Group Processes; Healed; Histone Acetylation; Histones; Human; Impaired cognition; Injury; Laboratories; Lateral; Lead; Limb structure; Link; Liquid substance; Lysine; Medical; Memory; Modeling; Molecular; Muscle; Nerve Growth Factor Receptors; Neural Pathways; Neuronal Plasticity; Neurons; Nociception; Norepinephrine; Operative Surgical Procedures; Outcome Measure; Pain; Pathway interactions; Percussion; Peripheral; Persistent pain; Pharmaceutical Preparations; Pharmacological Treatment; Population; Positioning Attribute; Posterior Horn Cells; Process; Protein Subunits; Proteins; Reagent; Receptors, Adrenergic, alpha-2; Regulation; Regulatory Pathway; Rodent Model; Role; Signal Transduction; Signaling Molecule; Skin Tissue; Soft Tissue Injuries; Spinal; Spinal Cord; Spinal cord posterior horn; Study models; Surgical incisions; TBI Patients; Techniques; Time; Tissues; Transferase; Translating; Trauma; Traumatic Brain Injury; Veterans; War; Work; alpha 2 agonist; cell type; chemokine; chronic pain; cognitive performance; disability; functional disability; functional outcomes; healing; improved; inhibitor/antagonist; injured; locus ceruleus structure; member; neurotrophic factor; noradrenergic; novel; novel strategies; opioid use; preclinical study; prevent; public health relevance; relating to nervous system; spontaneous pain; therapy design; tool; translational study

 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.

 产品说明： 在平民环境中遭受创伤后，战争伤害后的慢性疼痛和残疾 手术后出现的异常情况非常普遍与创伤性脑损伤（TBI）相关的慢性疼痛与外周损伤相结合是特别有问题的，我们没有经过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，在人类和动物中的观察表明，中枢下行去甲肾上腺素能回路和传入神经通路会聚在脊髓背角，以调节特定神经元群体内的持续神经可塑性变化。此外，表观遗传机制已经作为一组能够将这些内在（例如，下行疼痛调制）和获得（例如，来自组织破坏的神经输入）因素整合到细胞功能的持续变化中的过程而出现。这些过程被TBI和疼痛性损伤激活。神经可塑性相关的神经营养因子脑源性神经营养因子（BDNF）是脊髓表观遗传调节疼痛敏感化的关键部分。因此，该项目的主要目标是确定表观遗传机制及其靶基因在外周损伤后支持疼痛和相关变化中的作用，特别是在TBI的情况下。 在第一个目标中，我们评估了组织乙酰转移酶（HAT）抑制剂在啮齿动物模型中减轻软组织损伤（切口）、TBI和这些损伤的组合后的疼痛、残疾和认知功能障碍的假设。将使用一组全面的结局指标，重点关注伤害性感受、自发性疼痛、功能（步态）异常和认知（记忆）变化。药理学治疗将包括高选择性试剂和适合于转化使用的药物。 在第二个目标中，我们评估HAT抑制剂阻断组蛋白乙酰化和增强外周损伤、TBI和这些损伤的组合后疼痛相关趋化因子信号分子的脊髓表达的假设。我们专注于这一目标的调控一个关键的疼痛相关基因已知的表观遗传调控，BDNF。将确定通过组蛋白乙酰化调节该分子的表达以及BDNF在疼痛和功能结果中的直接作用。在第三个也是最后一个目标中，我们将评估通过α-2肾上腺素能受体作为TBI与研究中的脊髓神经可塑性变化之间的通路起作用的下行去甲肾上腺素能抑制的变化的作用。同样，在整个该目的中将使用适用于人类的选择性试剂。 在项目完成时，我们希望更好地了解TBI，外周损伤和损伤的组合如何导致慢性疼痛。在这个评估的过程中，我们将描述特定的表观遗传机制，基因靶点和下行调节途径在促成这种非常有问题的慢性疼痛形式中的作用。我们预计将在位置上计划翻译人类研究。