Astrocyte-TAAR1 & METH in HAND

星形胶质细胞-TAAR1

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：作为一种流行的精神兴奋剂，甲基苯丙胺 (METH) 的使用会产生持久、强烈的欣快效应，而甲基苯丙胺滥用在普通人群中很常见，大约 10-15% 的人类免疫缺陷病毒 - 1 (HIV)。 -1) 患者报告 METH 滥用会加重 HIV 相关神经认知障碍 (HAND) 的严重程度和发病机制。与神经炎症、星形胶质细胞活化、脑过热、氧化应激和兴奋性毒性一致，因此，METH 影响星形胶质细胞的多种功能，但其实现机制尚不清楚。最近，我们报道了痕量胺相关受体 1 (TAAR1)。 METH 信号传导的新型星形胶质细胞受体在本提案中，我们将研究 METH 介导的 TAAR1 调节和激活以及导致 HAND 恶化的下游效应。我们在本提案中的初步数据表明，pCREB 在星形胶质细胞-METH 信号传导中发挥着关键作用，最近，我们提出 HAND 中的 METH 滥用会调节星形胶质细胞-TAAR1 及其下游。通过 cAMP、[Ca2+]i、PKA/ERK、PKC 和 NF-kB 信号传导调节 CREB，这些途径在机制中发挥着关键作用。星形胶质细胞介导的神经毒性结果，包括线粒体损伤、氧化应激、兴奋性毒性和神经炎症。此外，我们建议星形胶质细胞-TAAR1作为HAND和METH合并症的新治疗靶点，我们将在目标1中对TAAR1的分子调节进行研究。目标 2 中复杂的细胞内信号通路改变星形胶质细胞功能，最后使用 HAND 相关动物模型将工作扩展到潜在的治疗途径目标 3。首先，我们将研究星形胶质细胞-TAAR1 的调节以及导致神经胶质增生和神经炎症的 cAMP 变化（目标 1：分子），将使用用病毒毒素激活的人星形胶质细胞，或表达病毒蛋白的星形胶质细胞，而无需使用 METH。 TAAR1-GFP 过表达模型将用于识别 TAAR1 特异性反应，我们将描述导致 METH 的星形胶质细胞-TAAR1 细胞内信号传导。最后，我们将评估 TAAR1 作为潜在的治疗靶点（目标 3：转化），我们采用离体、体外和体内相结合的细胞和分子方法。这些研究将对星形胶质细胞-TAAR1的调节、其在基于药物滥用的神经功能缺陷中的作用以及作为手部冰毒合并症的新治疗靶点产生更广泛的影响。