mechanisms of HIV and drug abuse pathogenesis in CNS

描述(申请人提供)：甲基苯丙胺(Meth)是一种精神刺激剂，在美国已经超过可卡因的使用量。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风险因素。冰毒会增加艾滋病毒/SIV病毒载量，并加剧艾滋病毒相关的神经认知障碍(HAND)。甲硫氨酸导致中枢神经系统高致病作用的细胞和分子机制尚不完全清楚。虽然许多研究已经直接评估了Meth和HIV病毒毒素对神经元的影响，但星形胶质细胞在Meth/HIV共病中的作用还没有得到充分研究。星形胶质细胞占中枢神经系统细胞的70%，发挥着维持中枢神经系统内环境平衡的重要功能。我们证明，Meth诱导星形胶质细胞中的HIV复制，抑制连环蛋白信号，并导致谷氨酸运输网络的失调。甲基介导的抑制-连环蛋白信号转导特别重要，因为这一途径对细胞间的通讯、生存和增殖至关重要，我们发现它调节兴奋性氨基酸转运体2(EAAT2)，而兴奋性氨基酸转运体2是主要的谷氨酸转运体，负责星形胶质细胞摄取~90%的谷氨酸。这一应用将集中在Meth和-catenin信号转导在Meth/HIV共病中的病毒学、功能和潜在的治疗方法。具体地说，我们建议确定Meth诱导HIV生产性复制的机制(目标1/病毒学)；确定Meth/-catenin轴对星形胶质细胞功能的影响(目标2/Function)；以及评估-Catenin途径的小分子调节剂克服Meth对HIV和星形胶质细胞功能的影响的能力(目标3/Treateutics)。总之，这些研究将为HIV/Meth共病提供新的机制见解，并加快针对Meth和HIV加重的神经发病机制的药物其他药物的开发，通过靶向-catenin途径的细胞保护特性。 与公共卫生相关：甲基苯丙胺是一种在艾滋病毒阳性人群中经常被滥用的药物。它会导致危险的行为，从而增加感染艾滋病毒的机会。一旦感染艾滋病毒，Meth滥用者比HIV+非Meth滥用者有更严重的神经认知障碍。我们建议在细胞和分子水平上研究机制，以了解Meth和HIV如何导致比任何一个单独的因素更差的临床结果。了解这些途径是设计治疗这种并存疾病的新策略的关键第一步。

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. PUBLIC HEALTH RELEVANCE: Methamphetamine is a drug that is often abused in the HIV+ population. It leads to risky behavior that increases the chances for HIV infection. Once HIV infected, Meth abusers have worse neurocognitive impairment than HIV+ non Meth abusers. We propose to study mechanisms at the cellular and molecular level to understand how Meth and HIV lead to worse clinical outcome than either factor alone. Understanding these pathways is a critical first step to devise novel strategies to treat this co-morbid condition.