LIPID MEDIATORS IN HIV NEUROTRANSMITTER DYSFUNCTION

hiv相关认知和运动缺陷的潜在机制，被称为艾滋病痴呆复合体（ADC），本质上可能是多因素的，因为这些缺陷与该疾病的病理指标之间没有明确的相关性。认知缺陷的自发恢复和抗逆转录病毒治疗的恢复表明，某些缺陷可能具有可逆的、非细胞毒性的病因学。我们假设，由于hiv感染的巨噬细胞（MF）对信号传导成分的作用，谷氨酸神经递质介导的细胞信号传导发生了改变；谷氨酸和谷氨酸受体的释放和摄取。具体来说，我们认为脂质介质（LM）花生四烯酸、血小板活化因子和前列腺素E2可引起谷氨酸能突触神经传递的可逆性变化。这些研究的目的是了解在hiv感染的大脑病理条件下产生的LM如何改变神经递质运输、释放和受体的特性，从而导致谷氨酸能细胞信号传导的变化。我们将通过尸检HIV-、HIV+、AIDS和ADC患者，初步研究大脑中关键LM合成酶的变化，并建立这些酶的诱导与谷氨酸转运变化之间的关联。新生儿大鼠脑的器官型海马切片与hiv感染的人Mf共培养，将用于模拟LM对突触信号综合成分的影响。我们将研究LM是否在模型系统中过量产生，以及LM的产生是否影响谷氨酸的摄取、释放、受体以及最重要的细胞信号传导。详细分析神经元中谷氨酸能细胞信号的变化将通过电生理学和钙成像研究进行研究。对LM介导的ADC非细胞毒性机制的了解可能为针对LM酶和受体的治疗策略提供建议。大脑的免疫特性、针对中枢神经系统的治疗方法的缺乏以及最近的抗逆转录病毒治疗失败的报道都表明，HIV相关的认知和运动缺陷可能会持续存在。这些发现可能与降低ADC的发病和严重程度特别相关。

The underlying mechanisms responsible for HIV-related cognitive and motor deficits, known as AIDS dementia complex (ADC), are probably multi-factorial in nature, as no clear correlation exists between these deficits and pathological measures in this disease. Spontaneous recovery from cognitive deficits and recovery with anti-retroviral therapy indicates that some deficit may have a reversible, non-cytotoxic etiology. We hypothesize that glutamate neurotransmitter-mediated cell signaling ius altered due to the actions of HIV-infected macrophages (MF) on components of signaling; release and uptake of glutamate and glutamate receptors. Specifically, we believe that the lipid mediators (LM) arachidonic acid, platelet activating factor and prostaglandin E2 can cause reversible changes in neurotransmission at the glutamatergic synapse. The goal of the proposed studies is to understand how LM generated under pathological conditions in the HIV-infected brain may alter properties of neurotransmitter transport, release and receptors, leading to changes in glutamatergic cell signaling. We will initially investigate changes in critical LM synthetic enzymes in brains from autopsy of HIV-, HIV+, AIDS, and ADC patients, and establish associations with induction of these enzymes and changes in glutamate transport. Organotypic hippocampal slices from neonatal rat brain co- cultured with HIV-infected human Mf will be used to model the effects of LM on the integrated components of synaptic signaling. We will investigate whether LM are produced in excess in the model system, and whether this LM production affects glutamate uptake, release, receptors and, most importantly, cell signaling. Detailed analyses of changes to glutamatergic cell signaling in neurons will be investigated with electrophysiology and calcium imaging studies. An understanding of possible LM-mediated non-cytotoxic mechanisms of ADC may suggest therapeutic strategies aimed at LM enzymes and receptors. The immune- privileged nature of the brain, paucity of CNS-targeted therapeutics and recent reports of anti-retroviral therapy failures all suggest that HIV- associated cognitive and motor deficits may continue to persist. These findings may be particularly relevant in reducing onset and severity of ADC.