突触外NR2B亚型NMDA受体在艾滋性认知功能障碍发病机制中作用的研究

艾滋性认知功能障碍(HAND)是重要艾滋病并发症。近年研究发现HIV-1病毒感染后很快进入大脑,但HAND发病因素与脑部病毒绝对水平无正相关, HIV-1感染的单核细胞产生的分泌物才是诱发HAND的致病因子。我们的前期研究发现:单核细胞趋化蛋白-1(MCP-1)是其中的重要致病因子,MCP-1损伤大鼠海马CA1区神经元结构并改变突触传递功能,而包括NR2B亚型在内的NMDA受体在此过程中起关键作用。因突触不同部位NMDAR在生理、病理上功能截然不同，我们下一步拟以表达NR2AR/NR2BR的爪蟾卵母细胞、艾滋病脑炎小鼠、大鼠海马脑片、培养海马细胞为研究对象,运用膜片钳、基因转录及蛋白表达、[Ca2+]i动态扫描、RT-PCR等技术,进一步研究突触外分布NR2B亚型NMDAR的过度激活在MCP-1诱发HAND过程中引起中枢神经系统损伤和认知功能障碍的作用及机制,为HAND的防治提供新的思路。

HIV-1-associated neurocognitive disorders(HAND) is an important AIDS complication. Recent studies have shown that HIV-1 virus enters the brain soon after infection, but HAND clinical appearance has no positive correlation with the absolute level of the HIV-1 in brain. The key for mechanism of HAND is that HIV-1-infected, immune activated mononuclear phagocytes secrete a variety of neurotoxins leading to neuronal dysfunction and death. Our previous studies found that: monocyte chemoattractant protein-1 (MCP-1) is one of the important pathogenic factors among these secretory substances. MCP-1 induce neuronal damage and change synaptic transmission in rat hippocampal Slices. And NR2B subtype of NMDA receptor plays a key role in this process. Recent observations have shown that the location of NMDAR makes the key difference; survival promoting signals derive from synaptic NMDARs, whereas a cell-death signal comes from extrasynaptic NMDAR, which contain mostly NR2BRs. So the extrasynaptic NR2BR could be a potential target for MCP-1 induced neuronal damage. To uncover the mechanisms for HAND pathogenesis and to identify potential therapeutic targets for HAND, we propose to investigate the role that extrasynaptic NR2BR might play in HIV associated neuropathology and its link to neuronal injury and cognitive decline. Based on our previous observations we intend to further characterize the effects of MCP-1 on NR2AR/NR2BR in Xenopus oocytes, AIDS encephalitis in mice, rat hippocampal brain slices, and cultured hippocampal neurons. Patch clamp, gene transcription, protein expression, [Ca2 +]i dynamic scanning, RealTime-PCR, and other technology may be used to further study the role that extrasynaptic NR2BR might play in MCP-1 induced HAND. By completion of the proposed studies, we will not only provide new insights into the mechanisms of HIV-1 neuropathogenesis, but also furnish new target for therapies in the prevention and treatment of HAND.