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：糖尿病患者和神经病患者报告了继发于糖尿病神经性疼痛（DNP）的生活质量大大降低。 DNP患者经历下肢燃烧或“冲击样的感觉”，对疼痛（痛觉过敏）和非刺激（异常性痛苦）的敏感性提高。尽管DNP的发病率很高，但对这种并发症的发作和进展的机制知之甚少。我们的目标是确定可以作为DNP治疗的治疗靶标的特定蛋白质。作为第一步，我们在2型糖尿病的遗传模型（DB/DB小鼠）中定量DNP。到8周龄时，这些小鼠会经历热和机械性异常。这些DNP的这些迹象与神经生长因子（NGF）上调，与背根神经节神经元（DRG）神经元中的p38激酶激活，随后的p38激酶激活和增加的物质P（SP）表达相对应。该建议将检验以下假设：DRG神经元中的NGF信号传导是2型糖尿病中糖尿病诱导的疼痛行为的发展。我们假设糖尿病增强的NGF表达激活DRG神经元上的TRKA受体，从而导致p38激酶-SP途径的下游激活。该途径的激活导致2型糖尿病动物模型和人类的DNP导致热痛觉过敏和机械性异常性。相关性：2型糖尿病正在增加美国的流行比例。 2型糖尿病的常见并发症是DNP。目前，DNP难以管理，并且负责严重的患者发病率和生活质量差。在此提案中，我们试图基于对该疾病的发病机理的更透彻的理解来确定DNP的新治疗靶标。