Biology of GDNF in Diabetic Neuropathy

糖尿病神经病变是一种在许多糖尿病患者中发展起来的严重神经并发症。小的 无髓鞘感觉纤维通常会受到影响，导致异常的皮肤感觉和疼痛。它是 认为相互关联的机制参与了糖尿病肾病的发生，神经营养支持不足是近年来研究的热点。 已被添加到可能的赤字清单中。小纤维糖尿病肾病患者的伤害性感觉神经元对 神经生长因子(NGF)或胶质细胞源性神经营养因子(GDNF)。鉴于研究发现 注意到糖尿病肾病患者NGF对感觉神经元的支持不足，对GDNF的作用知之甚少。长的- 这个项目的学期目标是在糖尿病的动物模型中，检查GDNF相关配体的生物学和 受体缺陷与糖尿病引起的生理和行为缺陷相关。我们的 目的是揭示糖尿病肾病发展的潜在机制，从而提供将 协助开发治疗糖尿病肾病的新疗法。 我们以前的研究表明，GDNF反应神经元的中枢突起对 糖尿病和GDNF的应用可以逆转GDNF反应的脊髓终末的缺陷。这项建议 将检验糖尿病和糖尿病患者GDNF对初级感觉神经元的支持受损的假说 GDNF反应神经元的解剖/生理缺陷可导致皮肤反应受损 刺激物。第一个特定目标将表征GDNF/GDNF-受体合成和转运的缺陷。 STZ诱导的糖尿病小鼠，并检测GDNF治疗是否能改善配体/受体的异常。 第二个目标将表征脊髓和皮肤中GDNF反应纤维的缺陷，然后测试 GDNF刺激感觉神经轴突生长和再神经支配的能力。最终的目标将是 通过对单个、已鉴定的GDNF反应神经元进行电生理记录而导致的神经元缺陷 体外皮肤神经制剂中的神经元。生理缺陷将与心脏功能异常相关 糖尿病小鼠对有害的机械、化学和热刺激的反应。GDNF的能力 还将测试修改神经元对皮肤刺激的生理学和行为反应。 总而言之，这笔赠款建议使用分子、解剖学、生理学和行为学方法来 了解GDNF在糖尿病肾病中的生物学作用，并检测其对皮肤是否有治疗作用。 糖尿病动物的神经元受到影响。这项研究的结果将提供1)GDNF受损的证据 支持有助于糖尿病肾病的发展和2)将GDNF确立为用于治疗的候选 改善糖尿病肾病患者的皮肤功能。

Diabetic neuropathy (DN) is a serious neural complication that develops in many diabetic patients. Small unmyelinated sensory fibers are commonly affected, leading to abnormal cutaneous sensation and pain. It is believed that interrelated mechanisms contribute to DN and insufficient neurotrophic support has recently been added to the list of possible deficits. Nociceptive neurons affected in small-fiber DN respond either to nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF). Whereas studies have noted deficits in NGF support to sensory neurons in DN, little is known about the role of GDNF. The long- term goal of this project is in an animal model of diabetes, examine the biology of GDNF-related ligands and receptors and correlate deficits with physiological and behavioral deficits that are caused by diabetes. Our purpose is to uncover mechanisms underlying the development of DN, thus providing information that will aid in developing novel treatments for DN. Our previous studies demonstrate that the central processes of GDNF-responsive neurons are sensitive to diabetes and GDNF administration can reverse deficits in GDNF-responsive spinal terminals. This proposal will test the hypotheses that GDNF support to primary sensory neurons is impaired in diabetes and anatomical/physiological deficits in GDNF-responsive neurons can lead to impaired responses to cutaneous stimuli. The first specific aim will characterize deficits in GDNF/GDNF-receptor synthesis and transport in STZ-induced diabetic mice, and test whether GDNF treatment can improve ligand/receptor abnormalities. The second aim will characterize deficits in GDNF-responsive fibers in the spinal cord and skin, and then test the ability of GDNF to stimulate sensory axon growth and reinnervation. The final aim will characterize deficits in GDNF-responsive neurons by performing electrophysiological recordings of single, identified neurons in an in vitro skin-nerve preparation. Physiological deficits will be correlated with abnormalities in the response of diabetic mice to noxious mechanical, chemical and thermal stimuli. The capacity of GDNF to modify neuronal physiology and behavioral responses to cutaneous stimuli will also be tested. In sum, this grant proposes to use molecular, anatomical, physiological and behavioral approaches to understand the biology of GDNF in DN and to test whether GDNF has therapeutic actions on cutaneous neurons affected in diabetic animals. Results from this study will 1) provide evidence that impaired GDNF support contributes to the development of DN and 2) establish GDNF as a candidate to be used in treatments to improve cutaneous function in DN.