Biology of GDNF in Diabetic Neuropathy

糖尿病神经病变（DN）是糖尿病患者常见的严重神经系统并发症.小 无髓鞘感觉纤维通常受到影响，导致异常的皮肤感觉和疼痛。是 认为相关的机制有助于DN和神经营养支持不足， 已被列入可能的赤字清单。在小纤维DN中受影响的伤害性神经元对以下两种刺激反应： 神经生长因子（NGF）或胶质细胞系衍生的神经营养因子（GDNF）。然而，研究表明， 尽管在DN中发现了NGF对感觉神经元支持的缺陷，但对GDNF的作用知之甚少。很长的- 该项目的长期目标是在糖尿病动物模型中，研究GDNF相关配体的生物学， 受体，并与糖尿病引起的生理和行为缺陷相关。我们 目的是揭示DN发展的潜在机制，从而提供信息， 有助于开发DN的新治疗方法。 我们以前的研究表明，GDNF反应神经元的中枢过程对 糖尿病和GDNF给药可以逆转GDNF反应性脊髓末梢的缺陷。这项建议 将检验GDNF对初级感觉神经元的支持在糖尿病中受损的假设， GDNF反应神经元的解剖/生理缺陷可导致对皮肤刺激的反应受损。 刺激。第一个具体的目标是表征GDNF/GDNF受体合成和转运的缺陷， STZ诱导的糖尿病小鼠，并测试GDNF治疗是否可以改善配体/受体异常。 第二个目标将描述脊髓和皮肤中GDNF反应纤维的缺陷，然后测试 GDNF刺激感觉轴突生长和神经再支配的能力。最终目标将体现 GDNF反应性神经元的缺陷，通过对单个，鉴定的 神经元在体外皮肤神经制备。生理缺陷将与 糖尿病小鼠对有害机械、化学和热刺激的反应。GDNF的能力， 还将测试对皮肤刺激的神经元生理学和行为反应的改变。 总而言之，这项资助计划使用分子、解剖、生理和行为方法， 了解GDNF在DN中的生物学作用，并检测GDNF是否对皮肤损伤具有治疗作用， 糖尿病动物的神经元受到影响。这项研究的结果将1）提供证据表明，受损的GDNF 支持有助于DN的发展和2）建立GDNF作为候选人用于治疗 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.