Cellular and Molecular Role of CXCR4 signaling in Painful Diabetic Neuropathy

摘要 糖尿病影响着美国2580万人。神经性疼痛是一种使人衰弱的痛苦， 糖尿病患者，对生活质量有很大影响。尽管有这种显著的影响和普遍性， 目前神经性疼痛的治疗仅部分有效， 糖尿病中的神经性疼痛还没有被很好地理解。 我们的长期目标是阐明负责PDN的分子机制，以提供 为开发有效治疗该综合征的治疗剂提供了靶点。 本申请的目的是鉴定连接CXCR 4/SDF-1的分子级联 趋化因子信号传导至DRG伤害感受器过度兴奋性、神经性疼痛和小纤维变性。的 研究的具体目标如下。 目的1：确定由以下物质产生的伤害感受器超兴奋状态的离子通道电流分布： PDN中的CXCR 4/SDF-1信令。 目标2.确定伤害感受器过度兴奋状态的基因表达谱， PDN中的CXCR 4/SDF-1信令。 目标3.确定伤害感受器线粒体功能障碍的具体特征， PDN中的CXCR 4/SDF-1信令。 这一提议的总体影响是更好地理解了 与糖尿病相关的神经性疼痛和小纤维变性。此外，拟议的研究 将通过确定独特的分子靶点， PDN的发展。

ABSTRACT Diabetes affects 25.8 million people in the USA. Neuropathic pain is a debilitating affliction present in 26% of diabetic patients, with substantial impact on the quality of life. Despite this significant impact and prevalence, current therapies for neuropathic pain are only partially effective and the molecular mechanisms underlying neuropathic pain in diabetes are not well understood. Our long-term goal is to elucidate the molecular mechanisms responsible for PDN in order to provide targets for the development of therapeutic agents for the effective treatment of this syndrome. The objective of this application is to identify the molecular cascade linking CXCR4/SDF-1 chemokine signaling to DRG nociceptor hyper-excitability, neuropathic pain, and small fiber degeneration. The study will achieve the following specific aims. Aim 1: Determine the ion-channel current profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN. Aim 2. Determine the gene expression profile of the nociceptor hyper-excitable state produced by CXCR4/SDF-1 signaling in PDN. Aim 3. Determine the specific features of nociceptor mitochondrial dysfunction produced by CXCR4/SDF-1 signaling in PDN. The overall impact of this proposal is a better understanding of the molecular underpinnings of neuropathic pain and small fiber degeneration associated with diabetes. Furthermore, the proposed research will have a positive impact by identifying unique molecular targets for mechanism-based therapeutic development in PDN.