GDNF AND NOCICEPTIVE PRIMARY SENSORY NEURONS IN DIABETES

描述：伤害性感觉神经元的一个重要亚群 (IB4/Ret神经元)最近被发现可以交换它们的神经营养素 神经生长因子(NGF)对胶质细胞系的要求 神经营养因子(GDNF)。IB4/Ret神经元对营养相当敏感 由于受伤而造成的剥夺。GDNF政府似乎逆转了 这些神经元的缺陷。这项提议将检验以下假设： IB4/Ret神经元易受糖尿病神经病变的影响 与其他糖尿病人群不同的是，他们对伤害的态度也不同。此信息 可能表明这些细胞对GDNF的治疗作用敏感， 而不是NGF。 具体目的是确定IB4/Ret神经元对 通过检测IB4/Ret表达的选择性标志物的变化来检测糖尿病 链脲佐菌素(STZ)诱导的小鼠神经元。这项研究将描述 神经生长因子反应性神经元(TrkA)和IB4/Ret神经元在脑内的差异 能够表达再生所需的基因，但 在糖尿病中被抑制。GAP-43和TA1基因表达的变化 A-微管蛋白将在TrkA和IB4/Ret群体中进行比较 切断轴突，STZ诱导的小鼠。胶质细胞源性神经营养因子或神经生长因子增强 这些基因在IB4/Ret神经元中的表达将通过提供 对STZ诱导的轴突切除小鼠的营养素。 这个项目的长期目标是分析感官的反应 神经元对实验性糖尿病的作用，并将这些结果与新的 有关受影响神经元的营养需求的信息，以设计治疗方案 对糖尿病肾病有较好的特异性。这项研究的结果将提供 具体证据表明感觉神经元对 糖尿病与其功能和神经营养反应有关，以及 建议将GDNF作为治疗糖尿病的候选药物 神经病。

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.