Chemokine Signaling in Diabetic Neuropathy

糖尿病神经病变中的趋化因子信号转导

• 批准号: 9064234
• 负责人: Daniela M Menichella
• 金额: $ 18.45万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064234
• 关键词: Ablation; Adult; Afferent Neurons; Animal Model; Animals; Antiviral Agents; Area; Award; Axon; CXCR4 Receptors; CXCR4 gene; Calcium; Cells; Chimeric Proteins; Confocal Microscopy; Data; Demyelinations; Development; Diabetes Mellitus; Diabetic Neuralgia; Diabetic Neuropathies; Diabetic mouse; Disease; Electrophysiology (science); Environment; Goals; Health; Image; Imagery; Imaging Techniques; Investigation; K-Series Research Career Programs; Laboratories; Literature; Maintenance; Mediating; Molecular; Molecular Biology; Monitor; Mus; Nervous system structure; Neuroglia; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pain; Pain Threshold; Pathogenesis; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Physiological; Prevalence; Proteins; Quality of life; Regulation; Research; Research Methodology; Role; Scientist; Shapes; Signal Transduction; Spinal Ganglia; Stimulus; Stromal Cell-Derived Factor 1; Syndrome; Testing; Training; Transgenic Mice; base; chemokine; chronic pain; diabetic; diabetic patient; effective therapy; in vivo; innovation; insight; interest; novel; novel therapeutics; pain behavior; painful neuropathy; prevent; research study; response; skills

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.

描述（由申请人提供）：糖尿病或疼痛糖尿病神经病（PDN）的神经性疼痛是26％的糖尿病患者的痛苦，对其生活质量产生了重大影响。尽管存在严重的患病率和影响，但当前的PDN疗法仅部分有效。此外，尚不清楚pdn的分子和电生理机制。神经性疼痛是由降低疼痛阈值的感觉神经元中持续的兴奋性引起的，因此在没有适当刺激的情况下会产生疼痛。感觉神经元在响应不同的分子（包括趋化因子）的响应中表现出持续和增强的兴奋性，这是一大批在神经系统中具有重要功能的蛋白质。特别是，我们实验室的研究暗示了基质来源的因子1（SDF-1）及其受体CXCR4在神经性疼痛的发病机理中，包括局灶性周围神经轴突脱髓鞘和抗病毒毒性神经病。然而，CXCR4/SDF-1信号在PDN发病机理中的作用尚不清楚。我的长期目标是确定塑造负责过渡到PDN的背根神经节（DRG）感觉神经元中持续兴奋性的分子和生理机制。该应用的目的是研究CXCR4/SDF-1介导的DRG神经元的分子和生理机制高脱位的PDN。中心假设是CXCR4/SDF-1信号传导介导了负责PDN的分子不同DRG神经元的亚型的钙涌入和兴奋性。提出的实验将实现以下特定目标。目标1：表征PDN发作之前和之后的II型糖尿病DRG中表达细胞的CXCR4和SDF-1。目标2：确定DRG感觉神经元中的CXCR4/SDF-1信号是否需要过渡到PDN。目的3：检查SDF-1在II型糖尿病DRG中对感觉神经元兴奋性的调节是创新的，因为趋化因子信号传导以前没有与糖尿病中神经性疼痛的发病机理有关。此外，这些实验的结果将增加我们对感觉神经元兴奋性的变化如何有助于诱导PDN的理解，这是有效治疗这种当前棘手且广泛苦难的关键障碍。