Nerve Growth Factor Signaling in Painful Diabetic Neuropathy

疼痛性糖尿病神经病变中的神经生长因子信号传导

• 批准号: 7661858
• 负责人: Hsinlin Thomas Cheng
• 金额: $ 17.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661858
• 关键词: Accounting; Admission activity; Age; American; Amputation; Animal Model; Animals; Burn injury; Complication; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Diabetic Neuralgia; Diabetic Neuropathies; Disease; Disease Progression; Epidemic; Esthesia; Gene Proteins; Genetic Models; Goals; Growth Factor Gene; Hospitals; Hyperalgesia; Incidence; Lower Extremity; MAPK14 gene; Mediating; MicroRNAs; Modeling; Morbidity - disease rate; Mus; Nerve Growth Factors; Neurons; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 1; Non-Insulin-Dependent Diabetes Mellitus; Pain; Pathogenesis; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Proteins; Public Health; Quality of life; Receptor Activation; Reporting; Research Personnel; Role; Secondary to; Shock; Signal Pathway; Signal Transduction; Spinal Ganglia; Staging; Stimulus; Substance P; Substance P Receptor; Testing; Thermal Hyperalgesias; Treatment Efficacy; United States; Up-Regulation; allodynia; base; cellular targeting; cost; db/db mouse; diabetic; diabetic patient; experience; foot; inhibitor/antagonist; man; mechanical allodynia; new therapeutic target; pain behavior; painful neuropathy; prevent; programs; protein expression; receptor; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Patients with diabetes and neuropathy report a significantly decreased quality of life secondary to diabetic neuropathic pain (DNP). Patients with DNP experience lower extremity burning or "shock-like sensations" with increased sensitivity to both painful (hyperalgesia) and nonpainful stimuli (allodynia). Despite the high morbidity of DNP, mechanisms underlying the onset and progression of this complication are poorly understood. Our goal is to identify specific proteins that could serve as therapeutic targets in the treatment of DNP. As a first step, we quantitated DNP in a genetic model of type 2 diabetes, the db/db mouse. By 8 weeks of age, these mice experience thermal and mechanical allodynia. These signs of DNP correspond with nerve growth factor (NGF) up-regulation, tropomysin-related kinase (Trk) A receptor activation, subsequent p38 kinase activation, and increased substance P (SP) expression in dorsal root ganglion (DRG) neurons. This proposal will test the hypothesis that NGF signaling in DRG neurons underlies the development of diabetes- induced pain behavior in type 2 diabetes. We hypothesize that diabetes-enhanced NGF expression activates TrkA receptors on DRG neurons, leading to downstream activation of p38 kinase-SP pathway. Activation of this pathway leads to thermal hyperalgesia and mechanical allodynia in animal models of type 2 diabetes and to DNP in man. RELEVANCE: Type 2 diabetes is increasing to epidemic proportions within the United States. A common complication of type 2 diabetes is DNP. Currently, DNP is difficult to manage and is responsible for significant patient morbidity and poor quality of life. In this proposal we seek to identify new therapeutic targets for DNP based upon a more thorough understanding of the pathogenesis of this disorder.

描述（由申请人提供）：项目总结：糖尿病和神经病变患者报告继发于糖尿病神经性疼痛（DNP）的生活质量显著降低。患有DNP的患者经历下肢烧灼感或“休克样感觉”，对疼痛（痛觉过敏）和非疼痛刺激（异常性疼痛）的敏感性增加。尽管DNP的发病率很高，但这种并发症的发病和进展机制仍知之甚少。我们的目标是确定特定的蛋白质，可以作为治疗DNP的治疗靶点。作为第一步，我们在2型糖尿病的遗传模型db/db小鼠中定量DNP。到8周龄时，这些小鼠经历热和机械异常性疼痛。DNP的这些体征对应于背根神经节（DRG）神经元中神经生长因子（NGF）上调、原溶酶相关激酶（Trk）A受体活化、随后的p38激酶活化和P物质（SP）表达增加。这项建议将测试的假设，神经生长因子信号在背根神经节神经元的基础上发展的糖尿病引起的疼痛行为的2型糖尿病。我们假设糖尿病增强的NGF表达激活DRG神经元上的TrkA受体，导致下游p38激酶-SP通路的激活。激活这一途径导致热痛觉过敏和机械异常性疼痛的动物模型中的2型糖尿病和DNP在man. RELEVANCE：2型糖尿病正在增加到流行病的比例在美国。2型糖尿病的常见并发症是DNP。目前，DNP难以管理，并导致患者发病率高和生活质量差。在这个建议中，我们寻求确定新的治疗目标DNP的基础上更彻底地了解这种疾病的发病机制。