Neuromolecular Basis for Pain in Burn Injury

 描述（由申请人提供）： 无论是在退伍军人事务部还是在美国人口中，都存在对与烧伤相关的疼痛的更有效的治疗的非常实质性的需求。我们的实验室拥有独特的专业知识，在钠通道及其结合伙伴的研究有关的疼痛，并在树突棘发育不良有关的疼痛。我们已经开发和校准了啮齿类动物的烧伤疼痛模型，并明确指出钠通道Nav1.7在烧伤后疼痛中起主要作用。我们还开发了一种独特的基因治疗平台，并表明我们可以敲除特定的钠通道亚型，改善神经损伤后的疼痛。靶向我们的临床前烧伤研究中确定的新分子，使用基因治疗方法，以及已批准用于人类其他神经适应症的小分子化合物，为烧伤退伍军人提供更有效的治疗选择。在这项研究中：我们将评估基因治疗敲除Nav1.3在烧伤中的治疗潜力，这是基于我们先前的发现，即DRG和脊髓背角中Nav1.3上调有助于神经性疼痛，并且Nav1.3的敲除导致创伤性神经损伤引起的疼痛减轻。 我们将通过以下证明来研究接触蛋白运输的中断是否减轻烧伤后的疼痛：a）接触蛋白-1与Nav1.3钠通道形成复合物，并促进功能通道插入细胞膜内;和B）接触蛋白-1在轴突切开后上调，并与神经瘤内轴突尖端的该通道共定位。 我们将在我们的烧伤模型中探索Nav1.6敲低在通过Nav1.6- siRNA治疗疼痛中的治疗潜力，作为我们发现烧伤后机械性疼痛的传入信号传递并不严重依赖于Nav1.8或Nav1.7的后续研究，Nav1.6不仅在DRG神经元中表达，而且还具有使其有助于重复动作电位放电的生物物理属性。 我们将测试通过全身给予FDA批准的PAK 1抑制剂FK 228靶向Rac 1通路是否可以阻断背角神经元上的树突棘发育不良并改善烧伤后的神经性疼痛，作为我们证明Rac 1介导的棘发育不良导致二度烧伤后神经性疼痛的后续研究。我们所有的研究都旨在开发与烧伤相关的慢性疼痛的新疗法。

 DESCRIPTION (provided by applicant): There is a very substantial need, both within the VA, and within the U.S. population, for more effective treatments for pain associated with burn injury. Our laboratory possesses unique expertise in the study of sodium channels and their binding partners as related to pain, and in dendritic spine dysgenesis as related to pain. We have developed and calibrated burn injury pain models in rodents, and have unequivocally indicted sodium channel Nav1.7 as playing a major role in pain after burn injury. We also have developed a unique gene therapy platform and have shown that we can knockdown specific sodium channel subtypes and ameliorate pain after nerve injury. Targeting of novel molecules identified in our pre-clinical burn injury studies usinga gene therapy approach, and a small molecule compound already approved for human use for other neurological indications, holds promise for more effective treatment options for Veterans with burn injuries. In this study: We will assess the therapeutic potential of gene therapy knockdown of Nav1.3 in burn injury by building upon our previous findings that Nav1.3 up-regulation in DRG and spinal cord dorsal horn contributes to neuropathic pain, and that knockdown of Nav1.3 results in attenuation of pain due to traumatic nerve injury. We will examine whether disruption of contactin trafficking attenuates pain after burn injury by building upon our demonstration that: a) contactin-1 forms a complex with Nav1.3 sodium channels and facilitates insertion of functional channels within the cell membrane; and b) contactin-1 is up-regulated following axotomy and co-localizes with this channel in axonal tips within neuromas. We will explore the therapeutic potential of Nav1.6 knockdown in the treatment of pain via Nav1.6- siRNA in our burn injury model as a follow up to our findings that afferent signal transmission of mechanical pain after burn injury is not critically dependent on Nav1.8 or Nav1.7, and that Nav1.6 is not only expressed in DRG neurons but also has biophysical attributes that poise it to contribute to repetitive action potential firing. We will test whethe targeting the Rac1 pathway through systemic administration of FDA-approved PAK1 inhibitor FK228, can block dendritic spine dysgenesis on dorsal horn neurons and ameliorate neuropathic pain after burn injury as a follow up to our demonstration that Rac1-mediated spine dysgenesis contributes to neuropathic pain following second-degree burn injury. All of our studies are aimed at development of new therapies for chronic pain associated with burn injury.