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)：项目摘要：糖尿病和神经病变患者报告继发于糖尿病神经病理性疼痛(DNP)的生活质量显著降低。DNP患者出现下肢灼热或“休克样感觉”，对疼痛(痛觉过敏)和非疼痛刺激(异位痛觉)的敏感度增加。尽管DNP的发病率很高，但这种并发症的发生和发展机制尚不清楚。我们的目标是确定可以作为治疗DNP治疗靶点的特定蛋白质。作为第一步，我们在2型糖尿病的遗传模型db/db小鼠中对DNP进行了量化。到了8周大的时候，这些小鼠会经历热痛和机械性痛觉过敏。DNP的这些信号与神经生长因子(NGF)上调、原肌酶相关激酶(Trk)A受体激活、随后的p38激酶激活以及背根节(DRG)神经元中P物质(SP)表达增加相对应。这项提议将检验这一假设，即背根神经节神经元中的NGF信号是2型糖尿病患者糖尿病诱导疼痛行为发展的基础。我们推测，糖尿病增强的NGF表达激活了DRG神经元上的TrkA受体，导致了p38激酶-SP通路的下游激活。在2型糖尿病的动物模型中，这一通路的激活会导致热痛敏和机械性超敏，在人类中会导致DNP。相关性：在美国，2型糖尿病的流行程度正在上升。2型糖尿病的常见并发症是DNP。目前，DNP很难管理，是患者发病率和生活质量下降的主要原因。在这项建议中，我们试图在更彻底地了解这种疾病的发病机制的基础上，确定DNP的新治疗靶点。