Chemokine Signaling in Diabetic Neuropathy

描述（由申请人提供）：糖尿病中的神经性疼痛或疼痛性糖尿病神经病变（PDN）是一种使人衰弱的痛苦，存在于26%的糖尿病患者中，对他们的生活质量有实质性影响。尽管存在这种显著的患病率和影响，但目前的PDN治疗仅部分有效。此外，PDN的分子和电生理机制还没有得到很好的理解。神经性疼痛是由感觉神经元的持续兴奋性引起的，其降低了疼痛阈值，使得在缺乏适当刺激的情况下产生疼痛。感觉神经元对包括趋化因子的不同分子的反应显示出持续和增强的兴奋性，趋化因子是在神经系统中具有重要功能的一大组蛋白质。特别是，我们实验室的研究表明，基质衍生因子-1（SDF-1）及其受体CXCR 4参与了几种动物模型中神经性疼痛的发病机制，包括局灶性外周神经轴突脱髓鞘和抗病毒毒性神经病。然而，CXCR 4/SDF-1信号转导在PDN发病机制中的作用尚不清楚。我的长期目标是确定在背根神经节（DRG）感觉神经元中形成持续兴奋性的分子和生理机制，这些神经元负责向PDN过渡。本申请的目的是研究CXCR 4/SDF-1介导的DRG神经元超兴奋性的分子和生理机制。中心假设是CXCR 4/SDF-1信号传导介导负责PDN的分子上不同的DRG神经元亚型中的钙内流和兴奋性增强。拟议的实验将实现以下具体目标。目的1：研究Ⅱ型糖尿病患者PDN发病前后DRG中CXCR 4和SDF-1的表达情况。目的2：确定DRG感觉神经元中CXCR 4/SDF-1信号传导是否是向PDN过渡的必要和充分条件。目标3：研究SDF-1对II型糖尿病DRG中感觉神经元兴奋性的调节，该研究具有创新性，因为趋化因子信号传导先前未涉及糖尿病神经病理性疼痛的发病机制。此外，这些实验的结果将增加我们对感觉神经元兴奋性变化如何促进PDN诱导的理解，PDN是有效治疗这种目前难以治疗和广泛存在的疾病的关键障碍。

DESCRIPTION (provided by applicant): Neuropathic pain in diabetes or Painful Diabetic Neuropathy (PDN) is a debilitating affliction present in 26% of diabetic patients with substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the molecular and electrophysiological mechanisms underlying PDN are not well understood. Neuropathic pain is caused by sustained excitability in sensory neurons which reduces the pain threshold, so that pain is produced in the absence of appropriate stimuli. Sensory neurons display sustained and enhanced excitability in response to different molecules including chemokine's, a large group of proteins with important functions in the nervous system. In particular, research from our laboratory has implicated stromal-derived-factor-1 (SDF-1) and its receptor CXCR4 in the pathogenesis of neuropathic pain in several animal models including focal peripheral nerve axon demyelination and antiviral toxic neuropathy. However, the role of CXCR4/SDF-1 signaling in the pathogenesis of PDN is unknown. My long term goal is to identify the molecular and physiological mechanisms that shape sustained excitability in Dorsal Root Ganglia (DRG) sensory neurons responsible for the transition to PDN. The objective of this application is to investigate molecular and physiological mechanisms of CXCR4/SDF-1 mediated DRG neurons hyper-excitability underlying PDN. The central hypothesis is that CXCR4/SDF-1 signaling mediates enhanced calcium influx and excitability in a subtype of molecularly distinct DRG neurons responsible for PDN. The proposed experiments will achieve the following specific aims. Aim 1: To characterize CXCR4 and SDF-1 expressing cells in type II diabetic DRG before and after onset of PDN. Aim 2: To ascertain if CXCR4/SDF-1 signaling in DRG sensory neurons is necessary and sufficient for transition to PDN. Aim 3: To examine the regulation of sensory neuron excitability by SDF-1 in type II diabetic DRG The proposed research is innovative because chemokine signaling has not been previously implicated in the pathogenesis of neuropathic pain in diabetes. Additionally, the outcomes of these experiments will add to our understanding of how changes in the excitability of sensory neurons contribute to the induction of PDN, which is a critical barrier to progression for effective treatment of this currently intractable and widespread affliction.