NEURONAL ACTIONS OF HOST FACTORS IN NEUROAIDS

描述(改编自申请者摘要)：本项目将重点关注 趋化因子在调节神经细胞内钙信号转导中的作用 以及兴奋性作为HIV-1感染中神经功能障碍的模型。 假设是HIV-1在中枢神经系统感染诱导了可溶性物质的释放 与神经趋化因子结合的趋化因子(IP-10、RANTES、MIP-1α、IL-8) 受体和激活信号转导通路，使正常 神经细胞对神经效应分子的反应。这可能涉及两个方面 MAP激酶的短期和长期激活。其结果可能是损害 神经元的正常生理反应，导致病理性 功能障碍。研究人员将利用啮齿动物的初级混合海马体 提供野生型和精选转基因动物的培养 解决四个具体目标：1)确定敏感性和 培养的啮齿动物海马神经元对急性应用趋化因子的反应； 2)明确神经趋化因子受体的信号转导途径 激活；3)确定急性趋化因子暴露是否改变神经元 对谷氨酸的反应性；以及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。 总体设计将解决急性和慢性趋化因子的影响 暴露在神经细胞功能上，并将包括检查两个不同的 神经元的种类，兴奋性谷氨酸能神经元和抑制性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.