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.

退伍军人神经和脊髓损伤、创伤性肢体截肢、 烧伤和周围神经病变因慢性疼痛和痉挛而严重受阻。当前的治疗方法 在许多情况下是无效或部分有效的，并可能使人上瘾。我们的中心已经发展得很稳健 具有独特能力的研究计划，以开发新的、更有效的和非成瘾的治疗方法 患有慢性疼痛和痉挛的退伍军人。我们的研究从分子生理学研究进展到 在体外和动物模型中，到干细胞来源的模型，如iPSCs和临床翻译研究，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的疾病 人口。我们现在将在下面总结的五个主要研究计划中进一步推进这一进展。 研究计划I：Nav1.7--从目标到疼痛治疗。我们已经提供了一种直接的联系 Nav1.7和人类疼痛障碍，并与辉瑞和生物遗传研究公司合作推进 口服生物利用型、Nav1.7选择性阻滞剂，用于治疗神经病理性疼痛。作为通往新技术的并行路线 止痛药，我们还将推进一项大规模的内部努力，以确定 人Nav1.7及其双重Nav1.7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一个高分辨率的支架。 研究计划II：疼痛弹性的分子遗传学。我们是全球分子中心 人类神经病理性疼痛的遗传模型IEM的遗传学研究，其中功能获得突变 Nav1.7产生导致疼痛的外周疼痛信号DRG神经元的深度超兴奋性。我们现在 计划对一个具有Nav1.7-S241T突变的家庭进行深入研究，该突变导致IEM，其个别成员 使用IPSC衍生的感官创新平台，每个人都表现出严重程度截然不同的疼痛 神经元，以及下一代测序，以识别和验证赋予疼痛韧性的等位基因变异。 研究计划III：疼痛药物治疗的额外靶点。我们的研究已经确定和 验证了Nav1.8和Nav1.9作为人类疼痛的额外靶点，并扩大了 与Na+通道突变相关的人类神经病理性疼痛障碍。我们将扩展我们的发现 CBZ作为钠通道阻滞剂/门控修饰剂的双重作用，从Nav1.7到Nav1.8，以建立 这一新概念的概括性。我们将建立一个蛋白质组学平台，以确定以下渠道合作伙伴 规范伤害性感受器内Nav1.9的贩运，这将推动我们走向筛查平台和 加强对这一与躯体和内脏疼痛有关的通道的了解。 研究计划IV：钠通道相关外周的神经保护策略 神经病。我们已经开始解开导致轴突变性的细胞通路。 外周神经病变，并已表明钠离子通道阻滞剂和钠/钙交换抑制剂可以 在体外拯救退化的轴突。我们将使用体外功能分析和体内转基因动物 模型，以促进我们对Nav1.7通道变体与 痛性周围神经病导致DRG神经元轴突变性，并将评估治疗 战略，目标是在临床翻译研究中实施这些战略。 研究计划V：迈向SCI中的翻译研究。我们的中心提供了 大量证据表明树突棘发育不良与过度兴奋性有很强的相关性 与脊髓损伤相关的紊乱，以及钠通道，特别是星形胶质细胞，在脊髓损伤形成中的作用。 神经胶质疤痕。我们将以rac1-pak1通路为靶点，我们已经将其与树突棘发育不全有关，并且 还研究了抑制轴突再生的机制，包括胶质瘢痕内的因素，与 制定更有效的策略来修复和保护受损的中枢神经系统。