HIV Neurotoxicity-Mechanism & Modulation by Cannabinoids

描述(申请人提供)：小胶质细胞的激活和神经元的兴奋性毒性被认为是经常伴随全身性ADS的神经退行性变的基础。大麻类药物是临床上非法使用并广泛用于艾滋病患者的药物，它调节兴奋性神经传递和兴奋性毒性。这项建议解决了HIV-1蛋白、趋化因子和大麻素如何影响小胶质细胞功能和谷氨酸能突触传递最终影响神经元存活的总体问题。提出了四个具体目标。1)HIV-1蛋白和趋化因子激活了小胶质细胞中一种新的趋化因子受体信号级联反应。这个级联的下游元件提供分支点来调节特定细胞功能的假设将得到检验。这一级联反应中的激酶和通道可能是改变HIV-1相关性痴呆病程的有用的药理靶点。2)兴奋性钙离子浓度升高使神经元质膜钙泵功能下降。钙泵活性的丧失会导致兴奋性神经变性，而增加的钙外流具有神经保护作用，这一假设将得到验证。质膜Ca~(2+)泵可能是坏死性和凋亡性细胞死亡途径之间的一个重要的串联点。3)在HIV-1相关性痴呆中，认知损害先于显性神经元丢失。小胶质细胞释放的神经毒素会导致功能性突触丧失的假设将得到验证。突触功能可能对较低浓度的神经毒素比细胞存活更敏感。4)大麻素对兴奋性毒性的保护作用，抑制新的功能性突触的形成及其对突触传递的脱敏作用。从耐受培养中撤出大麻素将揭示突触传递和内源性大麻素信号的代偿性变化，从而增加神经元对兴奋毒性刺激的敏感性的假设将得到检验。这些研究将阐明内源性大麻素在中枢神经系统应激反应中的作用以及外源性大麻素对突触可塑性的影响。除了更好地了解HIV-1的神经毒性和大麻类物质对其调节作用外，这些研究还将有助于更广泛地了解小胶质细胞中趋化因子的功能，钙清除在神经毒性中的作用，以及G蛋白偶联受体和神经毒素对突触功能的调节。

DESCRIPTION (provided by applicant): Activation of microglia and neuronal excitotoxicity are postulated to underlie the neurodegeneration that frequently accompanies systemic ADS. Cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, modulate excitatory neurotransmission and excitotoxicity. This proposal addresses the overall question of how HIV-1 proteins, chemokines, and cannabinoids influence microglial function and glutamatergic synaptic transmission to ultimately affect neuronal survival. Four specific aims are proposed. 1) HIV-1 proteins and chemokines activate a novel chemokine receptor signaling cascade in microglia. The hypothesis that downstream elements of this cascade provide branch points to modulate specific cellular functions will be tested. The kinases and channels in this cascade may be useful pharmacologic targets for altering the course of HIV-1 associated dementia. 2) Excitotoxic Ca2+ increases degrade the plasma membrane Ca2+ pump in neurons. The hypothesis that loss of Ca2+ pump activity contributes to excitotoxic neurodegeneration and that enhanced Ca2+ efflux is neuroprotective will be tested. The plasma membrane Ca2+ pump may be an important point of cross talk between the necrotic and apoptotic cell death pathways. 3) Cognitive impairment precedes overt neuronal loss in HIV-1 associated dementia. The hypothesis that neurotoxins released by microglia induce a loss of functional synapses will be tested. Synaptic function may be sensitive to lower concentrations of neurotoxins than cell survival. 4) Cannabinoids protect from excitotoxicity, inhibit the formation of new functional synapses and their effects on synaptic transmission desensitize. The hypothesis that withdrawal of cannabinoids from tolerant cultures will reveal compensatory changes in synaptic transmission and endocannabinoid signaling that increase neuronal sensitivity to excitotoxic stimuli will be tested. These studies will clarify the role of endocannabinoids in CNS stress responses and the effects of exogenous cannabinoids on synaptic plasticity. In addition to providing a better understanding of HIV-1 neurotoxicity and its modulation by cannabinoids, these studies will contribute more generally to understanding chemokine function in microglia, the role of Ca2+ clearance in neurotoxicity and the modulation of synaptic function by G-protein-coupled receptors and neurotoxins.