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: 8442301
• 负责人: Hsinlin Thomas Cheng
• 金额: $ 3.94万
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442301
• 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 Expression; 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）： 项目摘要：患有糖尿病和神经病变的患者报告称，继发于糖尿病神经性疼痛 (DNP) 后，生活质量显着下降。 DNP 患者会出现下肢烧灼感或“电击样感觉”，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，但人们对这种并发症发生和进展的机制知之甚少。我们的目标是确定可以作为 DNP 治疗靶点的特定蛋白质。第一步，我们对 2 型糖尿病遗传模型 db/db 小鼠中的 DNP 进行了定量。到 8 周龄时，这些小鼠会出现热和机械异常性疼痛。 DNP 的这些迹象与神经生长因子 (NGF) 上调、原霉素相关激酶 (Trk) A 受体激活、随后的 p38 激酶激活以及背根神经节 (DRG) 神经元中 P 物质 (SP) 表达增加相对应。该提案将检验以下假设：DRG 神经元中的 NGF 信号传导是 2 型糖尿病中糖尿病诱发的疼痛行为发展的基础。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 p38 激酶-SP 通路下游激活。该通路的激活会导致 2 型糖尿病动物模型出现热痛觉过敏和机械异常性疼痛，并导致人类出现 DNP。相关性：2 型糖尿病在美国的流行率正在上升。 2 型糖尿病的常见并发症是 DNP。目前，DNP 难以管理，导致患者发病率高且生活质量差。在本提案中，我们寻求在更全面了解 DNP 发病机制的基础上确定 DNP 的新治疗靶点。