Endogenous mechanisms of neuroprotection

HIV-1相关的神经系统疾病被认为是慢性炎症状态的结果，其中 病毒和细胞来源的可溶性神经毒性分子可引起神经元损伤和功能障碍。 我们假设HIV-1的神经毒性受到许多内源性途径和介质的抑制， 保护神经元例如，神经营养因子可以增加神经元的存活和功能 通过激活特异性受体（Trk受体）和随后启动信号级联。 因此，我们建议研究内源性神经保护途径，可能为我们提供新的 神经艾滋病的治疗策略这将通过两个具体目标来实现。在目标1中， 将重点关注与神经营养因子受体激活相关的信号通路，包括对 混合谱系激酶（MLK）-3、p38激酶和c-Jun NH 2末端抑制剂的神经保护作用 激酶（JNK）以及拟肽Trk配体。对神经元存活和功能的影响 将评估暴露于候选HIV-1神经毒素的受试者对单核细胞/小胶质细胞活化的影响。 在第二个目标中，我们将评估响应于抑制而被调节的细胞信号传导事件。 的MLK-3，使用药理学和遗传学方法。这些实验将利用 可用的显性失活突变体和MLK-3敲除小鼠（以遗传靶向MLK-3），以及 现有的药理学化合物和新的，高度特异性的MLK-3阻滞剂，将由我们的开发 商业伙伴。总的来说，这些研究将确定新的神经保护策略， 增强neuroAIDS中的神经元功能和存活。这些研究的结果将与 为了鉴定新的治疗药物， 目标..

HIV-1 associated neurologic disease is believed to be the result of a chronic inflammatory state, in which soluble neurotoxic molecules, of both viral and cellular origin, act to cause neuronal injury and dysfunction. We hypothesize that HIV-1 neurotoxicity is opposed by a number of endogenous pathways and mediators, which serve to protect neurons. For example, neurotrophins can augment neuronal survival and function through the activation of specific receptors (Trk receptors) and subsequent initiation of signaling cascades. We therefore propose to study endogenous neuroprotective pathways that may provide us with new therapeutic strategies for neuroAIDS. This will be achieved through two specific aims. In Aim 1, experiments will focus on signaling pathways associated with neurotrophin receptor activation, including analyses of the neuroprotective effects of inhibitors of mixed lineage kinases (MLK)-3, p38 kinase and c-Jun NH2 terminal kinases (JNK), as well as peptidomimetic Trk ligands. Effects on the survival and function of neurons exposed to candidate HIV-1 neurotoxins will be evaluated, as will effects on monocyte/microglial activation. In the second aim, we will evaluate the cell signaling events that are modulated in response to the inhibition of MLK-3, using both pharmacological and genetic approaches. These experiments will take advantage of available dominant negative mutants and MLK-3 knockout mice (to genetically target MLK-3), as well as extant pharmacologic compounds and new, highly specific MLK-3 blockers that will be developed by our commercial partner. Collectively, these investigations will identify novel neuroprotective strategies that may enhance neuronal function and survival in neuroAIDS. Results from these studies will be correlated with intracellular signaling events that occur in response to drug treatment, in order to identify new therapeutic targets..