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

描述(由申请人提供)：这项建议的目标是研究冰毒介导的微量胺相关受体1(TAAR1)的激活以及在冰毒相关的一过性高热背景下导致HIV-1相关神经认知障碍恶化的下游影响。作为一种精神刺激剂，使用甲基苯丙胺会产生强烈而持久的兴奋作用1。在此期间，甲基苯丙胺会提高性欲，损害判断力，并导致危险的性行为，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相关痴呆(HAD)3，由神经毒性机制介导，包括炎症、神经胶质细胞激活、兴奋性毒性、氧化应激和高热1、4-6。冰毒引起的体温高峰期在102-1030F/390℃之间，脑温度波动在10-40℃之间可能有助于神经退变机制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1，9对HIV-1相关的神经心理缺陷具有相加作用。我们表明星形胶质细胞对冰毒敏感，并假设微量胺相关受体1(TAAR1)介导了冰毒诱导的星形胶质细胞的效应。TAAR1是一种被痕量胺激活的G蛋白偶联受体，它启动细胞内环磷酸腺苷(CAMP)信号转导通路，调节基因表达和细胞反应。TAAR1是多巴胺转运体(DAT)调节、谷氨酸能信号转导和体温调节的重要神经元受体。我们认为，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，在手和冰毒相关的短暂性高热的背景下。我们将通过以下目的来解决这一假说：目的1研究星形胶质细胞TAAR1对METH/HIV-1ADA治疗及其相关的高温的调节作用，以及AIM 2，以阐明冰毒诱导的星形胶质细胞TAAR1激活和相关的一过性高温的下游信号通路，从而加重手的病理。这些研究的完成将有助于揭示HIV介导的神经变性和冰毒相关的短暂高热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.