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

METH/HIV-1 星形胶质细胞反应的调节：TAAR1

基本信息

批准号：
8732418
负责人：
Irma Cisneros
金额：
$ 3.05万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-11 至 2016-04-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8732418
关键词：
12 year old Address Agonist Amines Amphetamines Astrocytes Attenuated Behavioral Body Temperature Brain CCL2 gene Calcium Signaling Central Nervous System Infections Clinical Clinical Research Cognitive Complication Contracts Cyclic AMP Data Dementia Disease Dopamine Down-Regulation Elderly Epidemic Family Forskolin Functional disorder G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Gene Expression Regulation Generations Glutamates Goals HIV HIV-1 Heat shock proteins Heat-Shock Proteins 70 Heat-Shock Proteins 90 Hour Human Hyperthermia IL8 gene Individual Induced Hyperthermia Infection Inflammation Inflammatory Interleukin-6 Investigation Judgment Lead Libido Light Measures Mediating Messenger RNA Methamphetamine Methamphetamine dependence Mitochondria Molecular Morphology Motor Nerve Degeneration Neuraxis Neurocognitive Neuroglia Neurologic Neurons Outcome Oxidative Stress Pathology Patients Pharmaceutical Preparations Phenethylamines Physiologic Thermoregulation Physiological Process Production Proteins RNA RNA Interference Reactive Oxygen Species Recovery Regulation Reporting Risk Severities Signal Pathway Signal Transduction Signal Transduction Pathway Temperature United States Up-Regulation astrogliosis attenuation chemokine cytokine dopamine transporter excitotoxicity heat shock transcription factor high risk sexual behavior methamphetamine abuse methamphetamine exposure neuropsychological neurotoxic neurotoxicity novel psychostimulant public health relevance receptor research study response uptake

项目摘要

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.

描述（由申请人提供）：本提案的目的是研究 METH 介导的微量胺相关受体 1 (TAAR1) 的激活以及在 METH 相关背景下导致 HIV-1 相关神经认知障碍恶化的下游效应短暂的高热。作为一种精神兴奋剂，甲基苯丙胺 (METH) 的使用会产生强烈、持久的欣快效应 1。在此期间，甲基苯丙胺会增强性欲、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. 最严重的形式是 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、氧化应激和高温1、4-6。 METH 引起的高温峰值在 102-1030F/390C 之间，脑部温度波动在 10-40C 之间可能会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累加效应1, 9. 我们证明星形胶质细胞对 METH 敏感，并假设微量胺相关受体 1 (TAAR1)介导 METH 诱导的星形胶质细胞效应。作为一种由微量胺激活的 G 蛋白偶联受体，TAAR1 启动细胞内环磷酸腺苷 (cAMP) 信号级联，从而调节基因表达和细胞反应。 TAAR1 先前被确定为 METH 在多巴胺转运蛋白 (DAT) 调节、谷氨酰胺能信号传导和体温调节中发挥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 TAAR1，导致细胞内 cAMP 信号转导，进一步加剧 HAND 和 METH 相关短暂高热背景下星形胶质细胞介导的神经毒性。我们将通过以下目标来解决这一假设： AIM 1 研究星形胶质细胞 TAAR1 对 METH/HIV-1ADA 治疗和相关高热的调节反应，AIM 2 阐明 METH 诱导的星形胶质细胞 TAAR1 激活和相关短暂高热从而加剧的下游信号通路手病理学。这些研究的完成将揭示在 HIV 介导的神经变性和 METH 相关的短暂性高热期间星形胶质细胞中 TAAR1 特异性 cAMP 信号传导。