NEURONAL ACTIONS OF HOST FACTORS IN NEUROAIDS

描述（改编自申请人的摘要）：该项目将集中在 趋化因子在调节神经细胞内钙信号中的作用 和兴奋性作为HIV-1感染中神经功能障碍的模型。 假设中枢神经系统中的HIV-1感染诱导可溶性 结合神经元趋化因子的趋化因子（IP-10、RANTES、MIP-1 α、IL-8 受体和激活信号转导途径， 神经细胞对神经效应分子的反应。这可能涉及两个 MAP激酶短期和长期激活。结果可能是损害 神经元正常生理反应，导致病理性 功能障碍研究者将使用啮齿动物原代混合海马 提供了来自野生型以及选择的转基因动物的培养物， 解决四个具体目标：1）确定敏感性， 培养的啮齿动物海马神经元对急性应用的趋化因子的反应; 2)以确定参与神经元趋化因子受体的信号通路， 3）确定急性趋化因子暴露是否改变神经元的 对谷氨酸的反应性;和4）确定慢性 趋化因子暴露对神经元和星形胶质细胞电生理反应的影响。 整体设计将解决急性和慢性趋化因子的影响， 暴露于神经元细胞功能，并将包括两个不同的检查 神经元的类别，兴奋性谷氨酸能和抑制性GABA能神经元。

DESCRIPTION (Adapted from Applicant's Abstract): This project will focus on the role of chemokines in modulating neuronal cell intracellular calcium signaling and excitability as a model for neurological dysfunction in HIV-1 infection. The hypothesis is that HIV-1 infection in the CNS induces release of soluble chemokines (IP-10, RANTES, MIP-1 alpha, IL-8) which bind neuronal chemokine receptors and activate signal transduction pathways that subserve normal neuronal cell responses to neuroeffector molecules. This may involve both short-term and long-term activation of MAP kinase. The result may be impairment of normal physiological responses in neurons, resulting in pathological dysfunction. The investigator will utilize rodent primary mixed hippocampal cultures from wild-type as well as selected transgenic animals provided to address four specific aims: 1) to determine the sensitivity and response of cultured rodent hippocampal neurons to acutely applied chemokines; 2) to identify the signaling pathways involved in neuronal chemokine receptor activation; 3) to determine whether acute chemokine exposure alters neuronal responsiveness to glutamate; and 4) to determine the effects of chronic chemokine exposure on neuronal and astrocytic electrophysiological responses. The overall design will address effects of both acute and chronic chemokine exposure on neuronal cell function and will include examination of two distinct classes of neurons, excitatory glutamatergic and inhibitory GABAergic neurons.