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：
8516486
负责人：
Raghava Potula
金额：
$ 35.62万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516486
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. PUBLIC HEALTH RELEVANCE: Methamphetamine, a highly addictive stimulant abused by millions of Americans and is known to alter immune function and increase susceptibility to infection. Epidemiological studies indicate growing evidence of the association between METH abuse and an increased incidence of HIV-1 infections. However, the apparent causal interrelationship between METH abuse and susceptibility to HIV-1 infection or its progression are largely unknown. Current proposal aims to understand putative mechanisms of immune dysfunctions in the setting of METH abuse and HIV-1 infection.

描述（由申请人提供）：甲基苯丙胺（甲基苯丙胺）滥用会损害宿主的防御机制，并被认为可以增强宿主对感染的敏感性。 HIV-1滥用者中HIV-1感染的高发病率以及甲基甲基免疫系统的潜在影响强调了Meth-HIV-1合并症的临床意义。尽管滥用甲基毒化与免疫失调有关，但甲基苯丙胺暴露与无法引起保护性适应性免疫反应之间的因果关系仍然难以捉摸。获得的免疫力，特别是CD8+T细胞反应，在控制HIV-1感染中起关键作用。缺乏对甲基苯丙胺对控制HIV-1感染中获得的免疫反应的影响的理解值得将来考虑。我们的初步数据表明，在原代人T细胞中，甲基钙的暴露增加了与线粒体损伤和T细胞功能障碍相关的ROS产生的胞质钙水平。我们发现，甲基甲基的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，可能导致甲基介导的T细胞功能障碍。我们第一次表明，痕量胺相关受体（TAAR1，由胺激活的新型受体）在T细胞上刺激了TRIME，这意味着某些MECH效应可能归因于该受体的活性。使用体外（分子，生化和功能测定）和慢性病毒感染的体内动物模型（HIV-1脑炎的SCID小鼠模型和LCMV小鼠模型）的体外动物模型的结合，我们将长期暴露于METH上，我们将解决以下问题：（1）甲基甲基甲基甲基苯细胞生理学对Cellysiolyal ocochyrial nip cell cellial riCochrial alig cochrocochrial natirics ocochrial niricals niw saterial sycocochrial niricals natigrial synicsics？（2）甲基介导的线粒体功能障碍在T细胞上的基本机制和分子后果是什么，它们在细胞免疫细胞损伤中起什么作用？（3）甲基介导的免疫功能障碍对宿主适应性免疫反应对慢性病毒感染（HIV-1/LCMV感染）有何影响？我们将通过使用蛋白质组学和分子生物学方法来鉴定甲基甲基和描绘途径的线粒体底物。拟议的工作非常重要，因为它将有助于理解HIV-1和METH滥用对自适应免疫的综合作用的基本机制。基于这些研究的增强T细胞免疫的治疗方法将减少持续感染。公共卫生相关性：甲基苯丙胺是一种高度上瘾的刺激物，数以百万计的美国人滥用，众所周知会改变免疫功能并增加对感染的易感性。流行病学研究表明，越来越多的证据证明了甲基苯丙胺滥用与HIV-1感染发生率增加之间的关联。但是，在很大程度上未知，甲基苯丙胺滥用与易感性感染或其进展之间的明显因果关系。当前的建议旨在了解甲基滥用和HIV-1感染的免疫功能障碍的假定机制。