Astrocyte-TAAR1 & METH in HAND

星形胶质细胞-TAAR1

• 批准号: 9103076
• 负责人: Anuja Ghorpade
• 金额: $ 34.33万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9103076
• 关键词: AIDS/HIV problem; Address; Affect; Amines; Animal Model; Astrocytes; Brain; CREB1 gene; Ceftriaxone; Comorbidity; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease Outcome; General Population; Gliosis; Glutamates; HIV Envelope Protein gp120; HIV-1; HIV-associated neurocognitive disorder; Human; Hyperthermia; In Vitro; Inflammatory Response; Injury; Investigation; Lead; MAPK3 gene; Mediating; Mediator of activation protein; Methamphetamine; Mitochondria; Modeling; Molecular; NF-kappa B; Neurologic; Neurons; Neuropathogenesis; Outcome; Oxidative Stress; Pathway interactions; Patients; Play; Process; Regulation; Reporting; Role; Scheme; Severities; Signal Pathway; Signal Transduction; Stimulus; Substance abuse problem; Synapses; Therapeutic; Transgenic Animals; Translational Regulation; Viral Proteins; Work; base; brain tissue; excitotoxicity; in vivo; insight; methamphetamine abuse; methamphetamine use; neuroinflammation; neuropsychological; neurotoxic; neurotoxicity; new therapeutic target; novel; overexpression; protein expression; psychostimulant; public health relevance; receptor; response; therapeutic target; therapy outcome; virotoxins

 DESCRIPTION (provided by applicant): As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. While METH abuse is common in the general population, approximately 10-15% of human immunodeficiency virus-1 (HIV-1) patients report METH abuse. METH exacerbates the severity and onset of HIV-associated neurocognitive disorders (HAND). Both METH and HAND neuropathogenesis mechanistically concur with neuroinflammation, astrocyte activation, brain hyperthermia, oxidative stress and excitotoxicity. Thus, METH affects a multitude of astrocyte functions, yet the mechanism through which this is attained is unclear. Recently, we reported trace amine associated receptor 1 (TAAR1) as a novel astrocyte receptor for METH signaling. In this proposal, we will investigate METH-mediated regulation and activation of TAAR1 and the downstream effects that lead to exacerbation of HAND in the context of METH comorbidity. Our preliminary data in this proposal suggest a critical role of pCREB in astrocyte-METH signaling. Recently, TAAR1 has also emerged as a promising pharmacotherapeutic target. We propose that METH-abuse in HAND modulates astrocyte-TAAR1 and downstream signaling via cAMP, [Ca2+]i, PKA/ERK, PKC and NF-kB regulating CREB. These pathways play critical mechanistic role(s) in astrocyte-mediated neurotoxic outcomes, including mitochondrial damage, oxidative stress, excitotoxicity and neuroinflammation. Further, we propose astrocyte-TAAR1 as a novel therapeutic target in HAND and METH comorbidity. We will conduct investigations in the molecular regulation of TAAR1 in Aim 1, delineate the complex intracellular signaling pathways altering astrocyte function in Aim 2 and lastly extend the work to potential therapeutic avenues using a HAND relevant animal model in Aim 3. First, we will investigate the regulation of astrocyte-TAAR1 and following cAMP changes leading to gliosis and neuroinflammation (Aim 1: Molecular). Human astrocytes activated with virotoxins, or those expressing viral proteins, with/out METH will be used. TAAR1-GFP overexpression model will be used to identify TAAR1-specific responses. Next, we will delineate astrocyte-TAAR1 intracellular signaling leading to METH comorbidity in HAND (Aim 2: Signaling and function). Lastly, we will evaluate TAAR1 as a potential therapeutic target (Aim 3: Translational). Taken together, we employ a combined cellular and molecular approach with ex vivo, in vitro and in vivo studies that will have broader implication(s) for astrocyte-TAAR1 regulation, its role in substance abuse-based neurological deficits and as a novel therapeutic target for METH comorbidity in HAND.

 描述（由适用提供）：作为一种流行的心理刺激剂，甲基苯丙胺（甲基苯丙胺）的使用会导致持久，强烈的欣快效果。尽管甲基苯丙胺在普通人群中很常见，但大约10-15％的人类免疫缺陷病毒1（HIV-1）患者报告了甲基苯丙胺滥用。甲基会加剧与HIV相关的神经认知障碍（手）的严重程度和发作。 Meth和手神经病发生都与神经炎症，星形胶质细胞激活，脑热疗，氧化应激和兴奋性毒性同意。这是Meth会影响许多星形胶质细胞功能，但是实现这一目标的机制尚不清楚。最近，我们报道了痕量胺相关的受体1（TAAR1）作为用于METH信号的新型星形胶质细胞受体。在此提案中，我们将研究METH介导的TAAR1的调节和激活，以及在METH合并症的背景下导致手加剧的下游效应。我们在该提案中的初步数据表明，PCREB在星形胶质细胞-METH信号传导中的关键作用。最近，TAAR1也成为有前途的药物治疗靶标。我们提出，手中滥用的甲基滥用会通过CAMP（CA2+] I，PKA/ERK，PKC和NF-KB调节的Creb调节星形胶质细胞-TAAR1和下游信号传导。这些途径在星形胶质细胞介导的神经毒性结果中起关键的机理作用，包括线粒体损伤，氧化应激，兴奋性毒性和神经炎症。此外，我们将星形胶质细胞-TAAR1作为手和METH合并症的新型热靶标。 We will conduct investigations in the molecular regulation of TAAR1 in Aim 1, delineate the complex intracellular signaling pathways altering astrocyte function in Aim 2 and lastly extend the work to potential therapeutic avenues using a HAND relevant animal model in Aim 3. First, we will investigate the regulation of astrocyte-TAAR1 and following cAMP changes leading to gliosis and neuroinflammation (Aim 1: Molecular).用病毒毒素或表达病毒蛋白激活的人类星形胶质细胞将使用/OUT/OUT METH。 TAAR1-GFP过表达模型将用于识别TAAR1特异性响应。接下来，我们将描述导致甲基合并症的细胞内信号传导（AIM 2：信号传导和功能）。最后，我们将评估TAAR1作为潜在的治疗靶点（AIM 3：翻译）。综上所述，我们通过体外，体外和体内研究采用了组合的细胞和分子方法，对星形胶质细胞-TAAR1调节具有更广泛的影响，其在基于药物滥用的神经系统防御中的作用以及作为甲基合并症的新型治疗靶标。