PGC-1alpha and Reelin: new players in HAND progression.

总结 已经表明，携带HIV-1的患者会对细胞和组织造成损害，而这些细胞和组织并不直接 被病毒本身感染（例如神经元）。重要的是，这些变化包括被称为艾滋病毒相关的 神经退行性疾病（HAND）导致神经元功能丧失。 HAND是HIV-1患者临床管理中的一个突出问题，因为抑制 通过c-ART感染病毒不能完全阻断神经退行性变化。神经心理学研究 在相当大的比例中揭示认知改变（如空间和陈述性记忆的丧失） HIV-1感染患者的脑组织，以及从用c-抗HIV抗体治疗的HIV-1患者分离的死后脑组织的分析。 抗逆转录病毒疗法显示出神经退化的迹象。 在没有HIV-1感染神经元的情况下，已经提出了HAND的许多机制， 包括CNS中的间接炎症作用和从CNS中脱落的病毒蛋白（例如达特）的直接作用。 激活HIV-1感染细胞这些病毒蛋白通过几条途径进入神经元 提出了许多竞争机制的存在，可以有助于手，其中每一个都有其 律师它们在体内对临床疾病的相对贡献仍有待整理，这是一个很好的方法。 艾滋病研究中的一个突出问题。 其他神经退行性疾病的研究描述了cAMP反应元件结合（CREB）-1 蛋白质作为记忆的关键调节器。这些研究还表明，CREB蛋白表达的缺失 和磷酸化有助于神经认知障碍的发展，如空间和 声明性内存变更。 最近，我们获得的数据显示HIV-1达特对CREB蛋白磷酸化的明显影响 体外（原代人和小鼠神经元以及神经元细胞系SH-SY 5 Y）和体内 (in用达特注射小鼠，然后用咯利普兰[CREB的激活剂]处理）（参见背景和 初步结果）。这一发现令人兴奋，原因有二： (1)CREB蛋白和神经变性之间的相关性已经在文献中得到了很好的建立， 表明这可能是HAND中的一个重要贡献机制;以及 (2)可以获得可以特异性地恢复CREB蛋白水平和功能的试剂， 有机会在小鼠体内直接测试这种机制的贡献。 我们的假设是达特通过减少线粒体功能而导致神经变性， 通过CREB蛋白活性的降低介导。 我们建议在组织培养细胞和小鼠体内测试这一假设，并验证中间体 CREB蛋白的作用使用特定的CREB激活剂：咯利普兰。 因此，在这份修改后的申请中，我们提出了更具体和更有针对性的问题，使我们能够 进行额外的体外和体内研究，以确定达特导致 通过主要关注Tat-CREB功能来恢复这种丢失的陈述性记忆， 学习 这些研究的完成将首次确定HIV-1达特与认知障碍的关系 例如，学习缺陷和空间和陈述性记忆障碍，这是常见的艾滋病毒- 1患者以及老年人。使用干预（Rolipram）方法防止CREB丢失 功能将有助于建立一种新的治疗策略（高通量筛选），以减轻认知障碍 艾滋病毒/艾滋病患者中与HIV-1感染相关的损害。 （由于达特和BDNF之间的关系已被充分研究，我们将提出BDNF实验， 仅验证我们的假设）。 !

SUMMARY It has been shown that patients carrying HIV-1 accumulate damage to cells and tissues that are not directly infected by the virus itself (e.g. neurons). Importantly, these include changes known as HIV- Associated Neurodegenerative Disorder (HAND) leading to the loss of neuronal functions. HAND is an outstanding problem in the clinical management of HIV-1 patients, because suppression of infectious virus by c-ART does not completely block neurodegenerative changes. Neuropsychological studies disclose cognitive alteration (such as loss of Spatial and Declarative Memory) in a substantial proportion of HIV-1 infected patients, and analysis of post-mortem brain tissues isolated from HIV-1 patients treated with c- ART show signs of neurodegeneration. In the absence of HIV-1 infection of neurons, a number of mechanisms have been proposed for HAND, including indirect inflammatory effects in the CNS and direct effects of viral proteins (e.g. Tat) shed from activated HIV-1-infected cells. The fact that these viral proteins enter the neurons through several pathways suggest the presence of many competing mechanisms that can contribute to HAND, each of which has its advocates. Their relative contributions to clinical disease in vivo remain to be sorted out, and this is an outstanding problem in HIV research. Studies from other neurodegenerative diseases described the cAMP responsive-element binding (CREB)-1 protein as a Key Regulator of the Memory. These studies also showed that loss of CREB protein expression and phosphorylation contributes to the development of neurocognitive impairments such as Spatial and Declarative Memory Alteration. Recently, we have obtained data showing a clear-cut effect of HIV-1 Tat on CREB protein phosphorylation and function in vitro (primary human and mouse neurons and in the neuronal cell line, SH-SY5Y) and in vivo (in mice injected with Tat then treated with Rolipram [activator of CREB]) (see BACKGROUND AND PRELIMINARY RESULTS). This finding is exciting for two reasons: (1) A correlation between CREB protein and neurodegeneration has been well-established in the literature, suggesting that this may be a significant contributory mechanism in HAND; and (2) Agents are available which can specifically restore CREB protein levels and function, offering an opportunity to test directly the contribution of this mechanism in vivo in mice. Our hypothesis is that Tat contributes to neurodegeneration via reduction of mitochondrial function, mediated by a decrease in CREB protein activity. We propose to test this hypothesis in tissue culture cells and in vivo in mice, and verify the intermediate role of CREB protein using the specific CREB activator: Rolipram. Therefore, in this revised application, we asked more specific and focus questions that will allow us to perform additional in vitro and in vivo studies to determine the exact mechanisms used by Tat leading to the loss of Memory by focusing mainly on the Tat-CREB function and to restore this lost declarative memory and learning. Completion of these studies will determine for the first time involvement of HIV-1 Tat in cognitive disorders such as, Learning Deficit and Spatial & Declarative Memory Impairment that is commonly observed in HIV- 1 patients as well as in aged persons. Using an Intervention (Rolipram) approach to prevent CREB loss of functions will help establishing a new therapeutic strategy (high throughput screening) to mitigate cognitive impairments associated with HIV-1 infection in HIV/AIDS patients. (Since the relation between Tat and BDNF was amply studied, we will propose BDNF experiments to validate our hypothesis only). !