GDNF AND NOCICEPTIVE PRIMARY SENSORY NEURONS IN DIABETES

描述：一个重要的伤害感受神经元亚群 (IB4/Ret神经元）最近被发现可以转换它们的神经营养因子 从神经生长因子（NGF）到神经胶质细胞系衍生的 神经营养因子（GDNF）。 IB 4/Ret神经元对营养性刺激非常敏感， 因伤害而造成的剥夺。 GDNF给药似乎逆转了 这些神经元的缺陷。 本提案将检验以下假设： IB 4/Ret神经元易受糖尿病神经病变的影响， 与其他糖尿病人群相比， 这些信息 可能揭示这些细胞对GDNF的治疗作用敏感， 而不是NGF。 具体目的是确定IB 4/Ret神经元对 通过测量IB 4/Ret表达的选择性标记物的变化来检测糖尿病 链脲佐菌素（STZ）诱导的小鼠神经元。 该研究将描述 NGF反应神经元（trkA）和IB 4/Ret神经元之间的差异 表达再生所需基因的能力， 在糖尿病中受到抑制。 GAP-43和Ta 1基因表达的变化 将在TrkA和IB 4/Ret群体之间比较α-微管蛋白， 轴突切断的STZ诱导的小鼠。 GDNF或NGF增强细胞凋亡的能力， 这些基因在IB 4/Ret神经元中的表达将通过提供 神经营养因子对轴突切断的STZ诱导的小鼠的作用。 这个项目的长期目标是分析感官的反应， 神经元实验糖尿病和夫妇这些结果与新的 有关受影响神经元的营养需求的信息，以设计治疗方案 对DN有较好的特异性。 这项研究的结果将提供 具体的证据表明，感觉神经元具有不同的敏感性， 糖尿病与其功能和神经营养反应有关， 提示GDNF可作为治疗糖尿病候选药物 神经病变

DESCRIPTION: A significant subpopulations of nociceptive sensory neurons (IB4/Ret neurons) has been recently found to switch their neurotrophins requirements from nerve growth factor (NGF) to glial cell line-derived neurotrophic factor (GDNF). IB4/Ret neurons are quite sensitive to trophic deprivation caused by injury. GDNF administration appears to reverse the deficits in these neurons. This proposal will test the hypotheses that IB4/Ret neurons are vulnerable to diabetic neuropathy and they respond differently to injury than other populations in diabetes. This information may reveal that these cells are sensitive to therapeutic actions of GDNF, and not NGF. The specific aims are to determine the sensitivity of IB4/Ret neurons to diabetes by measuring changes in selective markers expressed by IB4/Ret neuron in streptozotocin (STZ)-induced mice. The study will characterize differences between NGF-responsive (trkA) and IB4/Ret neurons in their capacity to express genes that are required for regeneration but are suppressed in diabetes. Changes in gene expression for GAP-43 and Ta1 a-tubulin will be compared between TrkA and IB4/Ret populations in axotomized, STZ-induced mice. The ability of GDNF or NGF to enhance expression of these genes in IB4/Ret neurons will be tested by supplying trophins to axotomized, STZ-induced mice. The long-term goal of this project is to analyze the responses of sensory neurons to experimental diabetes and couple these results with new information about the trophic needs of affected neurons to design treatments with better specificity for DN. Results from this study will provide specific evidence tha sensory neurons have varied susceptibilities to diabetes related to their functions and neurotrophic responsiveness, and suggest GDNF as a candidate to be used in treatments for diabetic neuropathy.