Cocaine induced selective epigenetic and signaling pathways enhance HIV replicati

可卡因诱导选择性表观遗传和信号通路增强 HIV 复制

基本信息

批准号：
8330018
负责人：
Mudit Tyagi
金额：
$ 15.85万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8330018
关键词：
AIDS neuropathy Acquired Immunodeficiency Syndrome Address Affect Area Award Biological Assay Brain Cells Chromatin Cocaine Cocaine Abuse Column Chromatography Complex Critical Pathways Cytokine Signaling Deterioration Disease Outcome Drug Addiction Drug Targeting Drug abuse Drug usage Elongation Factor Ensure Epigenetic Process Event Excision Gene Expression Generations Genes Genetic Transcription Grant HIV HIV Long Terminal Repeat HIV-1 Highly Active Antiretroviral Therapy Histone H3 Illicit Drugs Immune system Individual Injection of therapeutic agent Intervention Knowledge Lead Luciferases Microarray Analysis Microglia Modification Molecular NF-kappa B NIH Program Announcements Nervous system structure Neuraxis Organ Outcome Pathogenesis Pathway interactions Patients Peripheral Pharmacologic Substance Phosphorylation Phosphotransferases Positive Transcriptional Elongation Factor B Process Proviruses RNA Splicing Regulation Research Research Personnel Role Science Serine Signal Pathway Signal Transduction Stimulus Testing Transcription Factor AP-1 United States Up-Regulation Viral Proteins Virus Diseases Virus Replication Western Blotting Work brain cell chemokine chromatin immunoprecipitation cocaine exposure cofactor drug addict drug of abuse env Gene Products experience genome-wide improved macrophage novel therapeutics promoter public health relevance response small hairpin RNA tat Protein transcription factor transmission process

项目摘要

DESCRIPTION (provided by applicant): Injection and non-injection drug use and abuse remain significant cofactors for HIV infection and transmission. The drugs of abuse such as cocaine has also been implicated in HIV-1-associated pathogenesis e.g. HAD, HAND. It has become clear that drugs of abuse, including cocaine can modify both cellular epigenetic and signaling pathways, which ultimately modulate the expression of several cellular genes. Therefore, it would not be surprising if the gene expressions of integrated human immunodeficiency virus (HIV) provirus's are also influenced with this type of stimuli. Although, HIV gene expression by cocaine until now is mainly attributed to up regulation of several chemokines, cytokines, signaling pathways and some of viral proteins (e.g. Tat and Env), however, the molecular mechanism such as changes in epigenetic and signaling pathways by drugs of abuse could explain better the continuous induction of several genes even after removal of drug of abuse, which is normally the case. In order to develop better understanding of the complex interplay between drugs of abuse and HIV replication, it is important to investigate the impact of drugs of abuse on HIV gene expression especially in brain cells, as brain is the target organ for both drugs of abuse and HIV. Cocaine is one of the most widely abused drugs in the United States, which both impair the normal functioning of brain cells and also activate HIV gene expression in central nervous system (CNS). As a result, HIV-infected individuals who abuse cocaine experience more severe and rapid onset of NeuroAIDS than non-abusing individuals. In this grant we will study the molecular mechanisms involved in the regulation of HIV gene expression and replication by cocaine in two primary macrophage cells, microglial (from brain) and peripheral macrophage (MDMs from PBMCs). Precisely, we will test the hypothesis that cocaine induces HIV replication by facilitating the recruitment of P-TEFb at HIV LTR via enhancing the phosphorylation of Histone H3 at serine 10 residue and through activation of specific transcription factors such as NF-kB and AP-1. These modifications ultimately contribute to more rapid deterioration of immune and nervous system, which is quite prevalent in drug addict HIV patients. Broader Impact: This work is expected to lead towards the discovery of new underlying molecular pathways, which could direct towards the new therapeutic strategies to address several adverse disease outcomes due to aberrant proviral gene expression and replication in drug addict HIV patients.

描述（由申请人提供）：注射和非注射药物的使用和滥用仍然是 HIV 感染和传播的重要辅助因素。可卡因等滥用药物也与 HIV-1 相关的发病机制有关。有，手。很明显，包括可卡因在内的滥用药物可以改变细胞表观遗传和信号传导途径，最终调节多种细胞基因的表达。因此，如果整合型人类免疫缺陷病毒（HIV）原病毒的基因表达也受到此类刺激的影响，也就不足为奇了。尽管到目前为止，可卡因对 HIV 基因的表达主要归因于几种趋化因子、细胞因子、信号通路和一些病毒蛋白（例如 Tat 和 Env）的上调，然而，分子机制如药物改变表观遗传和信号通路滥用药物可以更好地解释即使在消除滥用药物后仍会持续诱导几个基因，这通常是这种情况。为了更好地了解滥用药物和 HIV 复制之间复杂的相互作用，研究滥用药物对 HIV 基因表达（尤其是脑细胞）的影响非常重要，因为大脑是滥用药物和 HIV 复制的靶器官。艾滋病病毒。可卡因是美国滥用最广泛的药物之一，它不仅会损害脑细胞的正常功能，还会激活中枢神经系统 (CNS) 中的 HIV 基因表达。因此，滥用可卡因的艾滋病毒感染者比不滥用可卡因的人会经历更严重和更快的神经艾滋病发作。在这笔资助中，我们将研究可卡因在两种初级巨噬细胞（小胶质细胞（来自大脑）和外周巨噬细胞（来自 PBMC 的 MDM））中调节 HIV 基因表达和复制的分子机制。准确地说，我们将测试可卡因通过增强组蛋白 H3 在丝氨酸 10 残基处的磷酸化以及通过激活特定转录因子（如 NF-kB 和 AP-1）促进 HIV LTR 处 P-TEFb 的募集来诱导 HIV 复制的假设。。这些修饰最终导致免疫和神经系统更快恶化，这在吸毒成瘾的艾滋病毒患者中相当普遍。更广泛的影响：这项工作预计将导致新的潜在分子途径的发现，这可能会指导新的治疗策略，以解决由于吸毒成瘾的艾滋病毒患者中前病毒基因表达和复制异常而导致的几种不良疾病结果。