Cocaine in the Neuropathogenesis of HIV infection: Role of HDAC2

可卡因在 HIV 感染的神经发病机制中：HDAC2 的作用

基本信息

批准号：
8410634
负责人：
MADHAVAN P. NAIR
金额：
$ 36.36万
依托单位：
FLORIDA INTERNATIONAL 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：
2013-03-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8410634
关键词：
AIDS/HIV problem Abbreviations Acetylation Acquired Immunodeficiency Syndrome Animal Model Astrocytes Behavioral Binding Blood - brain barrier anatomy CREB1 gene Ca(2+)-Calmodulin Dependent Protein Kinase Calcium Cells Central Nervous System Diseases Clinical Research Cocaine Cocaine Abuse Cocaine Users Cognitive Contracts Coupled Cyclic AMP Response Element Dendritic Spines Development Disease Disease Progression Down-Regulation Drug Addiction Drug abuse Electrical Resistance Epigenetic Process Gene Expression Genes Goals Growth HDAC2 gene HIV HIV Infections HIV-1 Hippocampus (Brain)Histone Deacetylation Histones Human Impairment In Vitro Individual Infection Injection of therapeutic agent Liposomes Mediating Memory Memory impairment Microglia Modeling Modification Molecular Motor Neurocognitive Neurodegenerative Disorders Neuronal Plasticity Neurons Neuropathogenesis Patients Play Predisposition Proteins Publishing Rattus Regulatory Element Reporting Research Risk Factors Role Self Administration Small Interfering RNA Synaptic Transmission Synaptic plasticity Therapeutic Therapeutic Intervention Time Transcriptional Regulation Transfection Transferrin Transferrin Receptor Trichostatin A Up-Regulation Valproic Acid Virus chromatin modification chromatin remodeling cocaine use cognitive function density drug abuser drug of abuse gene repression histone acetyltransferase histone deacetylase 2 inhibitor/antagonist mouse model nanoformulation nervous system disorder nuclease public health relevance receptor mediated endocytosis response tat Protein therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Cocaine is a significant risk factor for contracting HIV-1 infection and subsequently developing AIDS. The proposed research is aimed to dissect the role of cocaine and HIV-associated epigenetic mechanisms in the development of HIV-associated neurocognitive disorders (HAND). In recent years, chromatin remodeling has emerged as an important regulatory mechanism for drug addiction and also in development of neurodegenerative disorders. In the current study, we will focus on HDAC2 since it is known to play a critical role in cognitive function by regulating the density of dendritic spines and influencing synaptic transmission in mature neurons. However, the role of HDAC2 in development of HAND is not elucidated yet in the context of cocaine. In our published and preliminary studies, we found that HIV-1 Tat protein and HIV-1 infection upregulate HDAC2 expression with concomitant downregulation of CREB and CamKIIa and 17 other genes that are known to regulate synaptic plasticity. Further we have shown for the first time that cocaine significantly upregulated HDAC2 gene expression and downregulated miR-155 and transfection with miR-155 significantly inhibited HIV infection. Accordingly, we hypothesize that cocaine acts a co-factor in neuropathogenesis of HIV infection by modulating HDAC2 expression in CNS cells leading to transcriptional repression of genes that regulate neuronal activity and synaptic plasticity. The specific goals are to determine: 1) whether cocaine in association with HIV-1 virus modulates HDAC2 which in turn negatively regulates synaptic plasticity/ memory genes in primary human microglia, hippocampal neurons and astrocytes thereby contributing to the progression of HAND; 2) whether inhibition of HDAC2 reverses the effects of cocaine and HIV-1 virus on neuronal plasticity genes and dendritic spine density and 3) can delivery of HDAC2 specific siRNA and miR-155 across the in vitro blood-brain barrier (BBB) model and in HIV-E SCID cocaine mouse model using transferrin coupled liposomal nanoformulation be explored as a therapeutic strategy for HAND. Thus, an understanding of cocaine and HIV-associated epigenetic changes and its implications in neuropathogenesis will have translational significance for therapeutic targeting and control of HAND in HIV-infected cocaine users.

描述（由申请人提供）：可卡因是感染 HIV-1 并随后发展为艾滋病的重要危险因素。拟议的研究旨在剖析可卡因和 HIV 相关表观遗传机制在 HIV 相关神经认知障碍 (HAND) 发展中的作用。近年来，染色质重塑已成为药物成瘾以及神经退行性疾病发展的重要调节机制。在当前的研究中，我们将重点关注 HDAC2，因为已知它通过调节树突棘的密度和影响成熟神经元的突触传递在认知功能中发挥关键作用。然而，在可卡因的背景下，HDAC2 在 HAND 发展中的作用尚未阐明。在我们已发表的初步研究中，我们发现 HIV-1 Tat 蛋白和 HIV-1 感染上调 HDAC2 表达，同时下调 CREB 和 CamKIIa 以及已知调节突触可塑性的其他 17 个基因。此外，我们首次发现可卡因显着上调 HDAC2 基因表达并下调 miR-155，并且转染 miR-155 显着抑制 HIV 感染。因此，我们假设可卡因通过调节 CNS 细胞中 HDAC2 的表达，导致调节神经元活动和突触可塑性的基因转录抑制，从而在 HIV 感染的神经发病机制中发挥辅助因子的作用。具体目标是确定：1）可卡因与 HIV-1 病毒相关是否会调节 HDAC2，进而负向调节原代人类小胶质细胞、海马神经元和星形胶质细胞中的突触可塑性/记忆基因，从而促进 HAND 的进展； 2) 抑制 HDAC2 是否可以逆转可卡因和 HIV-1 病毒对神经元可塑性基因和树突棘密度的影响，3) 能否跨体外血脑屏障 (BBB) 模型传递 HDAC2 特异性 siRNA 和 miR-155，以及在 HIV-E SCID 可卡因小鼠模型中，使用转铁蛋白偶联脂质体纳米制剂作为 HAND 的治疗策略进行探索。因此，了解可卡因和 HIV 相关的表观遗传变化及其对神经发病机制的影响对于感染 HIV 的可卡因使用者的 HAND 治疗靶向和控制具有转化意义。