Mechanism of immune dysregulation secondary to methamphetamine abuse.

甲基苯丙胺滥用继发的免疫失调机制。

基本信息

批准号：
8711414
负责人：
Raghava Potula
金额：
$ 37.1万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711414
关键词：
Address Affect American Amines Amphetamines Animal Model Antigens Apoptosis Apoptotic BCL2 gene Biochemical Bioenergetics Biological Biological Assay CD8B1 gene Calcium Cell Cycle Cell Death Cell physiology Cells Chronic Comorbidity Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytotoxic T-Lymphocytes Data Drug abuse Electron Transport Encephalitis Enzymes Epidemiologic Studies Event Flow Cytometry Functional disorder Future G-Protein-Coupled Receptors Gene Expression Generations HIV-1 Homeostasis Host Defense Mechanism Human Immune Immune System Diseases Immune response Immune system Immunity Immunosuppression Impairment In Vitro Incidence Infection Injury Interferon Type II Intervention Investigation Lead Lymphocytic choriomeningitis virus MAP Kinase Gene Measures Mediating Methamphetamine Mitochondria Modeling Molecular Oxidative Stress Oxidative Stress Induction Pathologic Pathway interactions Permeability Phosphorylation Play Post-Translational Protein Processing Predisposition Proteins Proteome Proteomics Public Health Recovery Research Role SCID Mice Sampling Secondary to Serum Signal Pathway Signal Transduction System T cell response T-Lymphocyte Testing Therapeutic Time Tissues Two-Dimensional Gel Electrophoresis Virus Diseases Work acquired immunity adaptive immunity base c-myc Genes caspase-3 cell mediated immune response clinically significant cytotoxic granzyme B heme oxygenase-1 high risk sexual behavior immune function in vivo innovation insight methamphetamine abuse methamphetamine exposure mitochondrial dysfunction mouse model novel oxidative damage perforin public health relevance receptor research study response stimulant abuse tandem mass spectrometry two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Methamphetamine (METH) abuse impairs host defense mechanisms and is thought to enhance host susceptibility to infections. High incidence of HIV-1 infection in METH abusers and potential effects of METH on the immune system underscore the clinical significance of METH-HIV-1 co-morbidity. Although METH abuse is implicated in dysregulation of immunity, the causal interrelationship between METH exposure and the inability to elicit protective adaptive immune response remains elusive. Acquired immunity, in particular CD8+T cell response, plays a pivotal role in control of HIV-1 infection. Lack of understanding of impact of METH abuse on acquired immune response in controlling HIV-1 infection warrants future considerations. Our preliminary data showed that METH exposure increased cytosolic calcium levels in primary human T cells leading to generation of ROS that correlated with mitochondrial injury and T cell dysfunction. We found that METH exposure altered gene expression regulating cell signaling, proliferation and differentiation, cell-mediated immune responses and transcriptional co-activation potentially contributing to METH-mediated T cell dysfunction. For the first time, we showed that trace amine associated receptor (TAAR1, a novel receptor activated by amines) is stimulated by METH on T cells implying that some of METH effects may be attributable to activity of this receptor. Using a combination of in vitro (molecular, biochemical and functional assays) and in vivo animal models of chronic viral infection (SCID mouse model for HIV-1 encephalitis and LCMV mouse model) chronically exposed to METH, we will address the following questions: (1) What are the pathophysiological effects of METH on T cell mitochondrial dynamics? (2) What are the underlying mechanisms and molecular consequences of METH-mediated mitochondrial dysfunction on T cells and what roles do they play in cell immune cell impairment? (3) What effects does METH-mediated immune dysfunction have on the host adaptive immune responses to chronic viral infections (HIV-1/LCMV infection)? We will identify mitochondrial substrates of METH and delineate pathways involved in these effects by using proteomic and molecular biological approaches. The proposed work is highly significant, as it will contribute to understanding of the underlying mechanisms of the combined effects of HIV-1 and METH abuse on adaptive immunity. Therapeutic approaches towards boosting T cell immunity based on these investigations will reduce persistent infection.

描述（由申请人提供）：滥用甲基苯丙胺（METH）会损害宿主的防御机制，并被认为会增加宿主对感染的易感性。 METH 滥用者中 HIV-1 感染的高发生率以及 METH 对免疫系统的潜在影响强调了 METH-HIV-1 共病的临床意义。尽管滥用冰毒与免疫失调有关，但冰毒暴露与无法引发保护性适应性免疫反应之间的因果关系仍然难以捉摸。获得性免疫，特别是 CD8+T 细胞反应，在控制 HIV-1 感染中发挥着关键作用。由于缺乏对滥用冰毒对控制 HIV-1 感染的获得性免疫反应的影响的了解，值得未来考虑。我们的初步数据表明，冰毒暴露会增加原代人类 T 细胞中的胞质钙水平，导致产生与线粒体损伤和 T 细胞功能障碍相关的 ROS。我们发现，冰毒暴露改变了调节细胞信号传导、增殖和分化、细胞介导的免疫反应和转录共激活的基因表达，可能导致冰毒介导的 T 细胞功能障碍。我们首次证明 T 细胞上的微量胺相关受体（TAAR1，一种由胺激活的新型受体）受到 METH 的刺激，这意味着 METH 的一些作用可能归因于该受体的活性。利用长期暴露于冰毒的体外（分子、生化和功能测定）和体内慢性病毒感染动物模型（HIV-1 脑炎 SCID 小鼠模型和 LCMV 小鼠模型）的组合，我们将解决以下问题：（ 1) METH 对 T 细胞线粒体动力学有哪些病理生理学影响？ (2) METH介导的线粒体功能障碍对T细胞的潜在机制和分子后果是什么？它们在细胞免疫细胞损伤中发挥什么作用？ (3) METH介导的免疫功能障碍对宿主对慢性病毒感染（HIV-1/LCMV感染）的适应性免疫反应有何影响？我们将使用蛋白质组学和分子生物学方法鉴定 METH 的线粒体底物并描绘参与这些效应的途径。拟议的工作非常重要，因为它将有助于理解 HIV-1 和冰毒滥用对适应性免疫的综合影响的潜在机制。基于这些研究的增强 T 细胞免疫力的治疗方法将减少持续感染。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Methamphetamine induces trace amine-associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation.

甲基苯丙胺诱导人 T 淋巴细胞中痕量胺相关受体 1 (TAAR1) 的表达：在免疫调节中的作用。

DOI：
发表时间：
2016-01
期刊：
影响因子：
5.5
作者：
Sriram, Uma;Cenna, Jonathan M;Haldar, Bijayesh;Fernandes, Nicole C;Razmpour, Roshanak;Fan, Shongshan;Ramirez, Servio H;Potula, Raghava
通讯作者：
Potula, Raghava

P2X4 receptor regulates alcohol-induced responses in microglia.

P2X4 受体调节小胶质细胞中酒精诱导的反应。