mechanisms of HIV and drug abuse pathogenesis in CNS

描述（由申请人提供）：甲基苯丙胺（甲基）是一种精神兴奋剂，在美国已超过可卡因的使用。药物滥用，特别是甲基苯丙胺的使用是艾滋病毒感染和疾病进展的一个风险因素。冰毒可增加HIV/SIV病毒载量，并加重HIV相关的神经认知障碍（HAND）。Meth导致CNS发病率升高的细胞和分子机制尚不完全清楚。虽然许多研究直接评估了甲基和HIV病毒毒素对神经元的影响，但星形胶质细胞的作用在甲基/HIV共病中研究不足，星形胶质细胞占CNS细胞的70%，并执行维持CNS稳态的重要功能。我们证明，甲基诱导艾滋病毒复制星形胶质细胞，抑制-连环蛋白信号，并导致谷氨酸转运网络失调。Meth-catenin信号传导的抑制是特别重要的，因为该途径对于细胞间的通信存活、增殖是至关重要的，并且我们表明它调节兴奋性氨基酸转运蛋白2（EAAT 2），这是负责星形胶质细胞约90%的谷氨酸摄取的主要谷氨酸转运蛋白。本申请将集中在病毒学，功能和潜在的治疗方法在th轴之间的甲基和-连环蛋白信号在甲基/艾滋病病毒共病。具体而言，我们建议确定机制，甲基诱导艾滋病毒的生产性复制（目的1/病毒学），确定甲基/ -连环蛋白轴的影响，对星形胶质细胞的功能（目的2/功能），并评估能力的小分子调节剂的-连环蛋白途径，以克服甲基对艾滋病毒和功能的星形胶质细胞（目的3/治疗）。总的来说，这些研究将提供新的机制的见解艾滋病毒/甲基共病，并加快药物治疗的发展，可以针对甲基和艾滋病毒加剧的神经发病机制，通过靶向细胞的-连环蛋白途径的保护特性。

DESCRIPTION (provided by applicant): Methamphetamine (Meth) is a psychostimulant that has exceeded cocaine use in the US. Drug abuse in general and Meth use in particular is a risk factor for HIV acquisition and disease progression. Meth enhances HIV/SIV viral load and exacerbates HIV associated neurocognitive disorders (HAND). The cellular and molecular mechanisms by which Meth leads to heightened pathogenesis in the CNS are not entirely clear. While a number of studies have directly assessed the impact of Meth and HIV viral toxins in neurons, the role of astrocytes, which make up to 70% of cells in the CNS and perform vital functions to maintain CNS homeostasis, is understudied in Meth/HIV co-morbidity. We demonstrate that Meth induces HIV replication in astrocytes, inhibits -catenin signaling, and leads to dysregulation in the glutamate transport network. Meth-mediated inhibition of -catenin signaling is particularly important because this pathway is critical for cell-to-cell communication survival, proliferation, and we show that it regulates Excitatory Amino Acid Transporter 2 (EAAT2), the predominate glutamate transporter responsible for ~90% of glutamate uptake by astrocytes. This application will focus on the virology, function, and potential therapeutics in th axis between Meth and -catenin signaling in Meth/HIV co-morbidity. Specifically, we propose to identify the mechanism by which Meth induces HIV productive replication (Aim 1/virology); determine the impact of Meth/ -catenin axis on the function of astrocytes (Aim 2/function); and assess the ability of small molecule modulators of the -catenin pathway to overcome Meth effects on HIV and function of astrocytes (Aim 3/therapeutics). Collectively, these studies will provide novel mechanistic insights into HIV/Meth co-morbidity and expedite the development of pharmacotherpies that can target Meth and HIV exacerbated neuropathogenesis by targeting the cellular protective properties of the -catenin pathway.