Nerve Growth Factor Signaling in Painful Diabetic Neuropathy

项目概述：糖尿病和神经病变患者报告继发于糖尿病神经性疼痛（DNP）的生活质量显著下降。DNP患者经历下肢灼烧或“休克样感觉”，对疼痛（痛觉过敏）和非疼痛刺激（异常性痛觉）的敏感性增加。尽管DNP的发病率很高，但这种并发症发生和发展的机制尚不清楚。我们的目标是鉴定出可以作为DNP治疗靶点的特异性蛋白。作为第一步，我们在2型糖尿病遗传模型db/db小鼠中定量测定DNP。到8周龄时，这些小鼠经历了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、原泌素相关激酶（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P物质（SP）表达增加相对应。这一提议将验证DRG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这一假设。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。该通路的激活导致2型糖尿病动物模型中的热痛觉过敏和机械异常性疼痛，并导致人类DNP。相关性：2型糖尿病在美国正日益成为流行病。2型糖尿病的一个常见并发症是DNP。目前，DNP难以管理，并导致严重的患者发病率和生活质量下降。在这个建议中，我们寻求在对这种疾病的发病机制有更深入的了解的基础上，确定DNP的新的治疗靶点。

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.