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

描述（由申请方提供）：本提案的目的是研究在MET相关短暂性高热的背景下，MET介导的痕量胺相关受体1（TAAR 1）激活以及导致HIV-1相关神经认知障碍加重的下游效应。作为一种精神兴奋剂，甲基苯丙胺（METH）的使用导致强烈，持久的欣快效应1。在此期间，METH提高性欲，损害判断力，并导致危险的性行为，最终增加获得人类免疫缺陷病毒（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、神经胶质活化、兴奋性毒性、氧化应激和高热1，4-6。METH诱导的高热峰值在102- 1030 F/390 C之间，脑温波动在10- 40 C之间，可能导致神经退行性机制7，8。在临床研究中，METH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产生叠加效应1，9。我们发现，星形胶质细胞是敏感的甲基和假设，微量胺相关受体1（TAAR 1）介导的甲基诱导的星形胶质细胞的影响。TAAR 1作为一种被微量胺激活的G蛋白偶联受体，启动细胞内环磷酸腺苷（cAMP）信号级联，从而调节基因表达和细胞反应。TAAR 1先前被鉴定为在多巴胺转运蛋白（DAT）调节、多巴胺能信号传导和体温调节中METH作用的重要神经元受体10-12。我们认为，METH激活星形胶质细胞TAAR 1，导致细胞内cAMP信号传导，进一步加剧了HAND和METH相关的短暂高热背景下星形胶质细胞介导的神经毒性。我们将通过以下目的来解决这个假设：目的1研究星形胶质细胞TAAR 1调节METH/HIV-1ADA治疗和相关的高热和目的2阐明下游信号通路的甲基诱导星形胶质细胞TAAR 1激活和相关的短暂高热，从而加剧手病理。这些研究的完成将揭示在HIV介导的神经变性和METH相关的短暂高热期间星形胶质细胞中TAAR 1特异性cAMP信号传导。

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.