HIV NEUROTOXICITY--MECHANISM & MODULATION BY CANABINOIDS

兴奋性毒性被认为是经常伴随全身性艾滋病的神经变性的基础。该提案解决了HIV-1蛋白、趋化因子和滥用药物如何影响谷氨酸能突触传递以及突触活动异常模式导致的Ca2+负荷如何引发神经毒性的总体问题。光学、电生理和基因转移技术将导向三个特定的目标。1)确定趋化因子和HIV-1包膜蛋白（gp120）对原代培养的小胶质细胞和神经元的影响。gp120会干扰小胶质细胞中趋化因子介导的信号传导，诱导释放刺激突触网络并产生神经元死亡的因子的假设将得到验证。这些实验将阐明小胶质细胞在HIV-1神经毒性中的作用，并可能确定可能影响艾滋病痴呆复合体病程的药理学靶点。2)确定大麻素对谷氨酸突触活性的影响。拟大麻药物对突触传递的抑制将作为激动剂功效的功能脱敏，部分激动剂的内在活性将取决于特定的突触，这一假设将被测试。这些研究将为大麻类药物的突触机制提供见解。3)线粒体在nmda诱导的Ca2+介导的神经毒性中的作用将被确定。nmda诱导的Ca2+负载进入线粒体的摄取可以被调节，并且降低基质Ca2+水平的条件将具有神经保护作用的假设将被测试。了解有毒Ca2+负载的命运以及如何调节封存将为更好地研究Ca2+诱导的细胞死亡提供工具，并可能确定神经保护的靶点。总的来说，这些研究专门针对了解艾滋病的神经毒性及其滥用药物的调节，此外，它们将有助于更广泛地理解趋化因子在中枢神经系统中的功能，g蛋白偶联受体对突触活性的调节以及有氧代谢和Ca2+稳态之间的关系。

Excitotoxicity has been postulated to underlie the neurodegeneration that frequently accompanies systemic AIDS. This proposal addresses the overall question of how HIV-1 proteins, chemokines and drugs of abuse influence glutamatergic synaptic transmission and how the Ca2+ load that results from aberrant patterns of synaptic activity triggers neurotoxicity. Optical, electrophysiological and gene transfer techniques will be directed toward three specific aims. 1) The effects of chemokines and the HIV-1 envelope protein (gp120) on microglia and neurons grown in primary culture will be determined. The hypothesis that gp120 will interfere with chemokine-mediated signaling in microglia, inducing the release of factors that excite synaptic networks and produce neuronal death will be tested. These experiments will clarify the role of microglia in HIV-1 neurotoxicity and may identify pharmacologic targets that could influence the course of AIDS dementia complex. 2) The effects of cannabinoids on glutamatergic synaptic activity will be determined. The hypothesis that inhibition of synaptic transmission by cannabimimetic drugs will desensitize as a function of agonist efficacy and intrinsic activity of partial agonists will be dependent upon the specific synapse will be tested. These studies will provide insight into the synaptic mechanisms of cannabimimetic drugs. 3) The role of the mitochondrion in NMDA-induced, Ca2+-mediated neurotoxicity will be determined. The hypothesis that the uptake of NMDA-induced Ca2+ loads into mitochondria can be modulated and that conditions that reduce matrix Ca2+ levels will be neuroprotective will be tested. Understanding the fate of toxic Ca2+ loads and how sequestration can be modulated will provide tools to better study Ca2+-induced cell death and may identify targets for neuroprotection. Overall, these studies are directed specifically towards understanding AIDS neurotoxicity and its modulation by drugs of abuse, in addition, they will contribute more generally to understanding chemokine function in the CNS, the modulation of synaptic activity by G-protein-coupled receptors and the relationship between aerobic metabolism and Ca2+ homeostasis.