Cellular and Molecular Role of CXCR4 signaling in Painful Diabetic Neuropathy

CXCR4 信号传导在疼痛性糖尿病神经病变中的细胞和分子作用

• 批准号: 10063579
• 负责人: Daniela M Menichella
• 金额: $ 34.56万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063579
• 关键词: Affect; Automobile Driving; CXCR4 Receptors; CXCR4 gene; Calcium; Cells; Data; Development; Diabetes Mellitus; Diabetic Neuralgia; Disease; Electrophysiology (science); Event; Fiber; Gene Expression Profile; Generations; Genetic Transcription; Glucose Intolerance; Goals; Healthcare; High Fat Diet; Hypersensitivity; Inflammatory; Investigation; Ion Channel; Knock-in Mouse; Knowledge; Lead; Link; Messenger RNA; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Nerve Degeneration; Neurons; Nociceptors; Obesity; Pain; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Population; Prevalence; Proteins; Quality of life; Receptor Signaling; Regulation; Research; Role; Series; Signal Transduction; Sodium Channel; Spinal Ganglia; Standard Model; Stress; Stromal Cell-Derived Factor 1; Symptoms; Syndrome; Technology; Testing; axonal degeneration; base; calcium indicator; chemokine; chemokine receptor; designer receptors exclusively activated by designer drugs; diabetes pathogenesis; diabetic; diabetic patient; effective therapy; excitotoxicity; feeding; insight; mechanical allodynia; mitochondrial dysfunction; molecular marker; mouse model; novel; novel therapeutic intervention; novel therapeutics; painful neuropathy; prevent; receptor; therapeutic development; transcriptomics

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.

抽象的 糖尿病在美国影响2580万人。神经性疼痛是一种令人衰弱的痛苦，其中26％ 糖尿病患者，对生活质量产生重大影响。尽管产生了重大影响和普遍性，但 当前的神经性疼痛疗法仅是部分有效的，并且是分子机制的 糖尿病的神经性疼痛尚不清楚。 我们的长期目标是阐明负责PDN的分子机制，以提供 开发治疗剂的靶标，以有效治疗该综合征。 该应用的目的是确定连接CXCR4/SDF-1的分子级联 趋化因子信号传导至DRG伤害感受器过度兴趣，神经性疼痛和小纤维变性。这 研究将实现以下特定目标。 AIM 1：确定由Nocteptor高脱离状态的离子通道电流轮廓 PDN中的CXCR4/SDF-1信号传导。 AIM 2。确定由Nocteptor超脱离状态的基因表达谱。 PDN中的CXCR4/SDF-1信号传导。 AIM 3。确定由伤害感受器线粒体功能障碍产生的特定特征 PDN中的CXCR4/SDF-1信号传导。 该提案的总体影响是更好地理解 神经性疼痛和与糖尿病有关的小纤维变性。此外，拟议的研究 通过确定基于机制的治疗的独特分子靶标，将产生积极的影响 PDN的开发。