Cocaine enhances HIV replication by inducing transcriptionally active chromatin s

可卡因通过诱导转录活性染色质增强 HIV 复制

基本信息

批准号：
8329932
负责人：
Mudit Tyagi
金额：
$ 19.81万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8329932
关键词：
AIDS neuropathy Acetylation Acquired Immunodeficiency Syndrome Acute Address Affect Biological Assay Brain Cells Chromatin Chromatin Structure Chronic Cocaine Cocaine Abuse Complex Critical Pathways Cytokine Signaling Deterioration Disease Outcome Doxycycline Drug Targeting Drug abuse Drug usage Ensure Enzymes Epigenetic Process Event Excision Feline Immunodeficiency Virus Gene Expression Generations Genes Genetic Transcription Grant HIV HIV Long Terminal Repeat HIV-1 Highly Active Antiretroviral Therapy Histone Acetylation Histone H3 Histone H4 Histones Illicit Drugs Immune system Individual Injection of therapeutic agent Intervention Knowledge Laboratories Lead Lentivirus Vector Microglia Modification Molecular Myeloid Cells Nervous system structure Neuraxis Organ Outcome Pathogenesis Pathway interactions Patients Peripheral Pharmacologic Substance Physiological Process Proviruses Regulation Role Signal Pathway Signal Transduction Stimulus Testing United States Up-Regulation Viral Viral Proteins Virus Diseases Virus Replication Work base brain cell cell type chemokine chromatin modification cofactor drug addict drug of abuse experience histone acetyltransferase improved macrophage novel therapeutics overexpression public health relevance research study small hairpin RNA transmission process verdin photosensitizer

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 epigenetics and signaling pathways, which ultimately modulate the expression of several cellular genes. Therefore, it would not be surprising if the gene expression of integrated HIV proviruses 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 epigenetic changes 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). Cocaine is known to modulate expression of several cellular genes via inducing selective chromatin modifications by regulating specific set of enzymes. We will investigate how gene expression of integrated HIV provirus is affected by cocaine induced selective core histones acetylations in primary macrophage cells. 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 epigenetic 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）：注射和非注射药物使用和滥用仍然是艾滋病毒感染和传播的重要辅助因子。可卡因等滥用药物也与HIV 1相关的发病机理有关，例如有手。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学和信号传导途径，这最终会调节几种细胞基因的表达。因此，如果综合HIV病毒的基因表达也受到这种刺激的影响，那就不足为奇了。但是，到目前为止，可卡因的HIV基因表达主要归因于对几种趋化因子，细胞因子，信号途径和某些病毒蛋白（例如Tat和Env）的调节，但是，分子机制（例如，滥用药物的表观遗传变化）等分子机制可以更好地解释几种基因的持续诱导，甚至可以解释滥用药物后，这是滥用药物的均可恢复正常的。为了更好地了解滥用药物和艾滋病毒复制药物之间的复杂相互作用，重要的是要研究滥用药物对艾滋病毒基因表达的影响，尤其是在脑细胞中，因为大脑是虐待药物和艾滋病毒药物的靶心器官。可卡因是美国最广泛滥用的药物之一，既损害了脑细胞的正常功能，又激活了中枢神经系统（CNS）中的HIV基因表达。结果，滥用可卡因的艾滋病毒感染者比非虐待个体更严重，更快地发作。在这项赠款中，我们将研究可卡因在两个原发性巨噬细胞中可卡因调节的分子机制，以及可卡因在两个原发性巨噬细胞中复制，即小胶质细胞（来自脑）和外周巨噬细胞（来自PBMC的MDMS）。已知可卡因可以通过调节特定的酶集来调节几个细胞基因的表达。我们将研究可卡因诱导的原代巨噬细胞中可卡因诱导的核心组蛋白乙酰化的基因表达如何影响。这些修饰最终导致免疫和神经系统的更快恶化，这在吸毒者HIV患者中非常普遍。更广泛的影响：这项工作有望导致发现新的表观遗传途径，这可能会引导新的治疗策略，以解决由于异常的前病毒基因表达和吸毒者HIV患者的复制而解决的几种不良疾病结果。