METH/HIV-1 Regulation of Astrocyte Responses: TAAR1 & Hyperthermia

描述（由申请人提供）：本提案的目的是研究甲基甲醚介导的微量胺相关受体1 （TAAR1）的激活以及在甲基甲醚相关的短暂性高温背景下导致HIV-1相关神经认知障碍恶化的下游效应。作为一种精神兴奋剂，甲基苯丙胺（冰毒）的使用会产生强烈而持久的欣快效果。在此期间，甲基苯丙胺会增强性欲，损害判断力，导致危险的性行为，最终增加感染人类免疫缺陷病毒（HIV-1）的风险1,2。最严重的形式，hiv相关性痴呆（HAD）3，是由神经毒性机制介导的，包括炎症、胶质细胞激活、兴奋性毒性、氧化应激和高温1,4 -6。冰毒引起的高温峰值在102-1030F/390C之间，脑温度波动在10- 40C之间可能有助于神经退行性机制7,8。在临床研究中，冰毒依赖通过加剧这些常见的神经炎症过程，对HIV-1相关的神经心理缺陷具有累加效应。我们发现星形胶质细胞对甲基安非他明敏感，并假设微量胺相关受体1 （TAAR1）介导甲基安非他明诱导的星形胶质细胞效应。作为一种被微量胺激活的g蛋白偶联受体，TAAR1启动细胞内环磷酸腺苷（cAMP）信号级联反应，从而调控基因表达和细胞反应。TAAR1先前被确定为甲基苯丙胺在多巴胺转运体（DAT）调节、谷氨酰胺能信号传导和体温调节中的重要神经元受体10-12。我们提出冰毒激活星形胶质细胞TAAR1导致细胞内cAMP信号进一步加剧星形胶质细胞介导的神经毒性在HAND和冰毒相关的短暂性高温的背景下。我们将通过以下目的来解决这一假设：目的1：研究星形胶质细胞TAAR1对甲基苯丙胺/HIV-1ADA治疗和相关热疗的调节；目的2：阐明甲基苯丙胺诱导的星形胶质细胞TAAR1激活和相关的短暂热疗从而加剧HAND病理的下游信号通路。这些研究的完成将揭示在hiv介导的神经变性和甲基甲醚相关的短暂高温过程中星形胶质细胞中TAAR1特异性cAMP信号。

DESCRIPTION (provided by applicant): The goal of this proposal is to investigate METH-mediated activation of trace amine associated receptor 1 (TAAR1) and the downstream effects that lead to exacerbation of HIV-1 associated neurocognitive disorders in the context of METH-associated transient hyperthermia. As a psychostimulant, methamphetamine (METH) use results in strong, long lasting euphoric effects 1. During which, METH heightens the libido, impairs judgment and leads to risky sexual behavior ultimately increasing the risk of acquiring human immunodeficiency virus (HIV-1) 1, 2. The most severe form, HIV-associated dementia (HAD)3, is mediated by neurotoxic mechanisms including inflammation, glial activation, excitotoxicity, oxidative stress, and hyperthermia 1, 4-6. METH-induced hyperthermia peaks between 102-1030F/390C and brain temperature fluctuations between 10- 40C may contribute to neurodegenerative mechanisms 7, 8. In clinical studies METH dependence has an additive effect on HIV-1 associated neuropsychological deficits by exacerbating these common neuroinflammatory processes 1, 9. We show that astrocytes are sensitive to METH and postulate that trace amine associated receptor 1 (TAAR1) mediates METH-induced effects in astrocytes. As a G-protein coupled receptor activated by trace amines, TAAR1 initiates intracellular cyclic adenosine monophosphate (cAMP) signaling cascades leading to regulation of gene expression and cellular responses. TAAR1 was previously identified as an important neuronal receptor for METH action in dopamine transporter (DAT) regulation, glutaminergic signaling and thermoregulation 10-12. We propose that METH activates astrocyte TAAR1 leading to intracellular cAMP signaling further exacerbating astrocyte-mediated neurotoxicity in the context of HAND and METH- associated transient hyperthermia. We will address this hypothesis through the following aims: AIM 1 To investigate astrocyte TAAR1 regulation in response to METH/HIV-1ADA treatment and associated hyperthermia and AIM 2 To elucidate downstream signaling pathways of METH-induced astrocyte TAAR1 activation and associated transient hyperthermia thereby exacerbating HAND pathology. Completion of these studies will shed light on TAAR1 specific cAMP signaling in astrocytes during HIV-mediated neurodegeneration and METH-associated transient hyperthermia.