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）：该提案的目的是研究MECH介导的痕量胺相关受体1（TAAR1）的激活，以及在与甲基相关的瞬态过度热皮肤中，导致HIV-1相关神经认知障碍加剧的下游效应。 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,神经胶质激活，兴奋性毒性，氧化应激和高温1，4-6。甲基苯甲酸甲酯诱导的高热峰在102-1030f/390c之间与10-40C之间的脑温度波动之间的峰值可能有助于神经退行性机制7，8。在临床研究中，MET依赖性具有对HIV-1相关的神经心理缺陷的添加效应，使这些常见的神经性神经症与促成抗相关性均与驱动器相关，以至于宣传驱动器1，我们显示该敏感性。受体1（TAAR1）介导了甲基甲基诱导的星形胶质细胞的作用。作为由痕量胺激活的G蛋白偶联受体，TAAR1启动细胞内环状腺苷单磷酸（CAMP）信号传导级联反应，从而调节基因表达和细胞反应。 TAAR1先前被鉴定为多巴胺转运蛋白（DAT）调节，谷氨酰胺能信号传导和温度调节的重要神经元受体10-12。我们提出METH会激活星形胶质细胞TAAR1，从而导致细胞内cAMP信号传导在手和相关的短暂性高温中进一步加剧星形胶质细胞介导的神经毒性。我们将通过以下目的解决这一假设：目的1以响应甲基胶质细胞TAAR1调节，以响应甲基/HIV-1ADA治疗和相关的高温和AIM 2，以阐明甲基甲基磷脂型TAAR1激活的下游信号传导途径，并相关的瞬态高温和相关的瞬态高温，从而恶化手部病理学。这些研究的完成将阐明在HIV介导的神经退行性过程和甲基相关的瞬时高温期间，星形胶质细胞中的TAAR1特异性cAMP信号传导。