Endogenous mechanisms of neuroprotection

神经保护的内源性机制

基本信息

批准号：
7891343
负责人：
HARRIS A GELBARD
金额：
$ 21.07万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7891343
关键词：
AIDS Dementia Complex AIDS neuropathy Antibodies Cell Death Cells Cessation of life Chronic Cognitive Data Disease Dominant-Negative Mutation Event Exposure to Functional disorder Gene Expression Generations Genetic Goals HIV-1 Immunoblotting In Vitro Individual Inflammatory Investigation JUN gene Knockout Mice Laboratories Ligands Light MAPK14 gene Measures Mediating Mediator of activation protein Mitogen-Activated Protein Kinases N-terminal Nerve Growth Factor Receptors Neurologic Neurologic Deficit Neuronal Dysfunction Neuronal Injury Neurons Neuroprotective Agents Neurotoxins Pathology Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Production Proteins Receptor Activation Regulation Signal Pathway Signal Transduction Specificity Synaptic Transmission T-Lymphocyte TdT-Mediated dUTP Nick End Labeling Assay Testing Viral Virus Replication cytokine in vivo inhibitor/antagonist kinase inhibitor mitogen-activated protein kinase p38 mixed lineage kinase 3 monocyte motor deficit neuronal survival neuroprotection neurotoxic neurotoxicity neurotrophic factor new therapeutic target novel novel therapeutics peptidomimetics prevent receptor research study response stress-activated protein kinase 1 transcription factor

项目摘要

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..

HIV-1 相关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 神经毒性受到许多内源性途径和介质的对抗，其作用是保护神经元。例如，神经营养素可以增强神经元的存活和功能通过激活特定受体（Trk 受体）并随后启动信号级联。因此，我们建议研究内源性神经保护途径，这可能为我们提供新的途径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，实验将重点关注与神经营养素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 NH2 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 神经毒素的情况，以及对单核细胞/小胶质细胞激活的影响。在第二个目标中，我们将评估响应抑制而调节的细胞信号传导事件 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（以基因靶向 MLK-3），以及现有的药理化合物和新的、高度特异性的 MLK-3 阻滞剂将由我们开发商业伙伴。总的来说，这些研究将确定新的神经保护策略，这些策略可能会增强神经艾滋病患者的神经元功能和存活率。这些研究的结果将与响应药物治疗而发生的细胞内信号传导事件，以确定新的治疗方法目标..