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.

在神经和脊髓损伤的退伍军人中，康复以及生活质量，创伤性肢体截肢， 烧伤损伤和周围神经病受到慢性疼痛和痉挛的严重阻碍。当前治疗 在许多情况下，无效或部分有效，并且可能是额外的。我们的中心发展了强大 具有独特能力的研究计划，可以开发出新颖，更有效和非依恋的治疗方法 慢性疼痛和痉挛的退伍军人。我们的研究已经从分子生理研究中进行 体外和动物模型，用于干细胞衍生的模型，例如IPSC和临床翻译研究，以及 从罕见的人类家族疾病，提供遗传模型到影响更广泛的更常见疾病 人群。现在，我们将在下面总结的五个主要研究计划中以这一进展为基础。 研究计划I：NAV1.7 - 从目标到治疗的疼痛。我们提供了直接联系 NAV1.7和人类疼痛障碍，并与辉瑞和Biogen合作，以推进有关的临床研究 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。作为通往新的平行路线 止痛药，我们还将以大规模的内部努力向前迈进 人NAV1.7和双NAV1.7的分子确定剂。 卡马西平，该卡马西平应为理性药物设计提供高分辨率的支架。 研究计划II：疼痛弹性的分子遗传学。我们是全球分子枢纽 IEM的遗传研究是人类神经性疼痛的遗传模型，其中功能获得突变的突变 NAV1.7产生引起疼痛的周围疼痛信号DRG神经元的深度过度刺激性。我们现在 对一个导致IEM的NAV1.7-S241T突变的家庭的深入计划，其个人成员 使用IPSC衍生的感官的创新平台，每种表现疼痛都具有明显不同的严重程度 神经元和下一代测序，以识别和验证会议疼痛弹性的等位基因变体。 研究计划III：疼痛药物治疗的其他目标。我们的研究已经确定， 经过验证的NAV1.8和NAV1.9作为人类疼痛的其他目标，并扩大了范围 与Na+通道中突变有关的人类神经性疼痛障碍。我们将扩展我们的发现 CBZ作为NA+通道阻滞剂/门控修饰符的双重动作，从NAV1.7到NAV1.8 这个新颖概念的概括性。我们将建立一个蛋白质组学平台，以确定渠道合作伙伴 规范NAV1.9在伤害感受器中的贩运，这将使我们朝着筛选平台和 增进对该渠道的理解，该渠道已在体细胞和内脏疼痛中实施。 研究计划IV：钠通道相关周围的神经保护策略 神经病。我们已经开始解开有助于轴突变性的细胞途径 周围神经病，并表明Na+/Ca2+交换器的Na+通道阻滞剂和抑制剂可以 在体外营救退化轴突。我们将使用体外功能测定和体内转基因动物 模型，以促进我们对NAV1.7通道变体相关的机制的理解 疼痛的周围神经病导致DRG神经元轴突变性，并将评估治疗 策略的目的是在临床翻译研究中实施它们。 研究计划V：迈向SCI转化研究。我们的中心提供了 树突状脊柱失调与过度兴奋性之间存在很强的相关性证据 与SCI相关的疾病，以及钠通道的作用，尤其是在星形胶质细胞中，在形成中 神经胶质疤痕。我们将针对Rac1-Pak1途径，该途径已在树突状脊柱失调中实施，并且 还研究抑制轴突再生的机制，包括神经胶质疤痕内的因素， 制定更有效的策略来维修和保护受伤的中枢神经系统。