Center for Restoration of Nervous System Function

神经系统功能恢复中心

• 批准号: 10275481
• 负责人: Sulayman D Dib-Hajj
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10275481
• 关键词: Affect; Afferent Neurons; Analgesics; Animal Model; Astrocytes; Axon; Biological Assay; Burn injury; Carbamazepine; Cicatrix; Clinical; Clinical Research; Dendritic Spines; Development; Disease; Drug Design; Familial disease; Family; Genetic Models; Genetic study; Goals; Human; In Vitro; Individual; Lead; Link; Molecular; Molecular Genetics; Mutation; Nerve; Nerve Fibers; Nervous System Physiology; Neurons; Nociceptors; Oral; Pain; Pain Disorder; Pain management; Pathway interactions; Peripheral Nervous System Diseases; Pharmacotherapy; Physiological; Population; Precision therapeutics; Proteomics; Quality of life; Rehabilitation therapy; Research; Resolution; Role; Route; Severities; Sodium Channel; Spinal cord injury; Structure; Time; Transgenic Animals; Variant; Veterans; Visceral pain; abuse liability; addiction; axon regeneration; axonal degeneration; central nervous system injury; channel blockers; chronic pain; chronic pain management; gain of function mutation; genetic variant; human model; improved; in vivo; induced pluripotent stem cell; inhibitor; innovation; limb amputation; member; next generation sequencing; novel; novel therapeutic intervention; pain signal; painful neuropathy; peripheral pain; programs; repair strategy; resilience; restoration; scaffold; screening; spasticity; stem cell model; trafficking; translational study; treatment strategy

Rehabilitation, as well as quality of life, in Veterans with nerve and spinal cord injury, traumatic limb amputation, burn injury, and peripheral neuropathy is severely hampered by chronic pain and spasticity. Current treatments in many cases are ineffective or partially effective, and can be addictive. Our Center has developed robust research programs with unique capabilities to develop novel, more effective, and non-addictive treatments for Veterans with chronic pain and spasticity. Our research has progressed from molecular physiological studies in vitro and in animal models, to stem cell-derived models such as iPSCs and clinical translational studies, and from rare human familial disorders that provide genetic models to more common disorders that affect broader populations. We will now build on this progress in the five major research programs summarized below. Research Program I: Nav1.7—From Target to Therapy for Pain. We have provided a direct link between Nav1.7 and human pain disorders, and collaborated with Pfizer and Biogen to advance clinical studies of orally-bioavailable, Nav1.7-selective blockers for the treatment of neuropathic pain. As a parallel route to new pain medications, we will also move forward with a large-scale in-house effort to identify the atomic structure of human Nav1.7 and the molecular determinants of the dual Nav1.7 blocking/gating modifying action of carbamazepine, which should provide a high-resolution scaffold for rational drug design. Research Program II: Molecular Genetics of Pain Resilience. We are a worldwide hub for molecular genetic studies on IEM, a genetic model of human neuropathic pain, in which gain-of-function mutations of Nav1.7 produce profound hyperexcitability of peripheral pain-signaling DRG neurons that cause pain. We now plan in-depth study of a family with the Nav1.7-S241T mutation that causes IEM, whose individual members each manifest pain with distinctly different severity, using an innovative platform of iPSC-derived sensory neurons, and next-generation sequencing to identify and validate allelic variants that confer pain resilience. Research Program III: Additional Targets for Pain Pharmacotherapy. Our studies have identified and validated Nav1.8 and Nav1.9 as additional targets for pain in humans, and have expanded the spectrum of human neuropathic pain disorders associated with mutations in Na+ channels. We will extend our findings of a dual action of CBZ as a Na+ channel blocker/gating modifier, from Nav1.7 to Nav1.8 to establish the generalizability of this novel concept. We will build a proteomics platform to identify channel partners that regulate trafficking of Nav1.9 within nociceptors, which will advance us toward screening platforms and enhance understanding of this channel, which has been implicated in both somatic and visceral pain. Research Program IV: Neuroprotective Strategies in Sodium-Channel Related Peripheral Neuropathies. We have started to unravel the cellular pathways that contribute to axonal degeneration in peripheral neuropathies, and have shown that Na+ channel blockers and inhibitors of Na+/Ca2+ exchanger can rescue degenerating axons in vitro. We will use in vitro functional assays, and in vivo transgenic animal models, to advance our understanding of the mechanisms by which Nav1.7 channel variants associated with painful peripheral neuropathy lead to degeneration of axons of DRG neurons, and will assess treatment strategies with the goal of implementing them in clinical translational studies. Research Program V: Advancing Toward Translational Studies in SCI. Our Center has provided substantial evidence for!a strong correlation between dendritic spine dysgenesis and hyperexcitability disorders associated with SCI, and for a role of sodium channels, especially in astrocytes, in the formation of glial scars. We will target the Rac1-Pak1 pathway, which we have implicated in dendritic spine dysgenesis, and also investigate mechanisms that inhibit axonal regeneration, including factors within the glial scar, with the goal of developing more effective strategies for repair and protection of the injured CNS.

患有神经和脊髓损伤、创伤性截肢的退伍军人的康复和生活质量， 烧伤和周围神经病变受到慢性疼痛和痉挛的严重阻碍。 在许多情况下是无效或部分有效的，并且可能会让人上瘾。 具有独特能力的研究项目，可开发新颖、更有效且不成瘾的治疗方法 我们对患有慢性疼痛和痉挛的退伍军人的分子生理学研究取得了进展。 体外和动物模型，干细胞衍生模型，如 iPSC 和临床转化研究，以及 从提供遗传模型的罕见人类家族性疾病到影响更广泛的更常见疾病 我们现在将在以下总结的五个主要研究计划中继续取得这一进展。 研究计划 I：Nav1.7——从目标到疼痛治疗 我们提供了两者之间的直接联系。 Nav1.7 和人类疼痛疾病，并与辉瑞和百健合作推进临床研究 口服生物可利用的 Nav1.7 选择性阻滞剂，用于治疗神经性疼痛作为新的并行途径。 止痛药方面，我们还将推进大规模的内部工作，以确定其原子结构 人类 Nav1.7 和 Nav1.7 双重阻断/门控修饰作用的分子决定因素 卡马西平，它应该为合理的药物设计提供高分辨率的支架。 研究计划 II：疼痛抵抗力的分子遗传学 我们是全球分子遗传学中心。 IEM 的遗传学研究，IEM 是人类神经性疼痛的遗传模型，其中功能获得性突变 Nav1.7 使外周疼痛信号 DRG 神经元产生严重的过度兴奋，从而引起疼痛。 计划对一个具有导致 IEM 的 Nav1.7-S241T 突变的家族进行深入研究，该家族的个体成员 使用 iPSC 衍生的感觉创新平台，每种疼痛的严重程度明显不同 神经元和下一代测序来识别和验证赋予疼痛恢复能力的等位基因变异。 研究计划 III：我们的研究已经确定并确定了疼痛药物治疗的其他目标。 验证 Nav1.8 和 Nav1.9 作为人类疼痛的附加目标，并且具有扩展的范围 与 Na+ 通道突变相关的人类神经性疼痛疾病我们将扩展我们的发现。 CBZ 作为 Na+ 通道阻断剂/门控调节剂的双重作用，从 Nav1.7 到 Nav1.8，以建立 我们将建立一个蛋白质组学平台来识别渠道合作伙伴。 调节伤害感受器内 Nav1.9 的贩运，这将推动我们走向筛选平台和 增强对该通道的了解，该通道与躯体和内脏疼痛有关。 研究计划四：钠通道相关外周神经保护策略 我们已经开始解开导致轴突变性的细胞途径。 周围神经病变，并表明 Na+ 通道阻滞剂和 Na+/Ca2+ 交换器抑制剂可以 我们将使用体外功能测定和体内转基因动物来拯救退化的轴突。 模型，以加深我们对 Nav1.7 通道变体与相关机制的理解 疼痛性周围神经病变导致 DRG 神经元轴突变性，将评估治疗 策略，目标是在临床转化研究中实施它们。 研究计划五：推进 SCI 转化研究。 大量证据表明树突棘发育不全与过度兴奋之间存在很强的相关性 与 SCI 相关的疾病，以及钠通道的作用，特别是在星形胶质细胞中，在形成 我们将针对与树突棘发育不全有关的 Rac1-Pak1 通路，以及 还研究了抑制轴突再生的机制，包括神经胶质疤痕内的因素， 开发更有效的策略来修复和保护受伤的中枢神经系统的目标。