LIPID MEDIATORS IN HIV NEUROTRANSMITTER DYSFUNCTION

HIV相关认知和运动障碍的潜在机制，称为艾滋病痴呆复合体(ADC)，本质上可能是多因素的，因为这些缺陷与这种疾病的病理指标之间没有明确的相关性。认知障碍的自发恢复和抗逆转录病毒治疗的恢复表明，某些缺陷可能有可逆的、非细胞毒性的病因。我们假设谷氨酸神经递质介导的细胞信号改变是由于HIV感染的巨噬细胞(MF)对信号成分的作用；谷氨酸和谷氨酸受体的释放和摄取。具体地说，我们认为脂质介体(LM)花生四烯酸、血小板激活因子和前列腺素E_2可以引起谷氨酸能突触神经传递的可逆性变化。这项拟议研究的目的是了解在HIV感染的大脑中，在病理条件下产生的LM如何改变神经递质的运输、释放和受体的特性，从而导致谷氨酸能细胞信号的变化。我们将首先研究HIV-、HIV+、AIDS和ADC患者尸检中大脑中关键的LM合成酶的变化，并建立这些酶的诱导和谷氨酸运输的变化之间的联系。从与HIV感染的人MF共培养的新生大鼠脑中提取的器官型海马片将被用来模拟LM对突触信号整合成分的影响。我们将调查在模型系统中是否产生过量的LM，以及这种LM的产生是否影响谷氨酸的摄取、释放、受体，以及最重要的是，细胞信号。将通过电生理学和钙成像研究来详细分析神经元中谷氨酸能细胞信号的变化。对LM介导的ADC可能的非细胞毒性机制的了解可能有助于针对LM酶和受体的治疗策略。大脑的免疫特权性质，缺乏针对中枢神经系统的治疗方法，以及最近关于抗逆转录病毒治疗失败的报道，所有这些都表明，艾滋病毒相关的认知和运动缺陷可能会继续存在。这些发现可能在减少ADC的发病和严重程度方面特别相关。

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.