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

• 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
• 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

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）：可卡因是收缩HIV-1感染并随后发展艾滋病的重要危险因素。拟议的研究旨在剖析可卡因和与HIV相关的表观遗传机制在与HIV相关的神经认知疾病（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，我们将专注于HDAC2，因为众所周知，它通过调节树突棘的密度并影响成熟神经元的突触传播在认知功能中起关键作用。但是，在可卡因的背景下，HDAC2在手发展中的作用尚未阐明。在我们发表的初步研究中，我们发现HIV-1 TAT蛋白和HIV-1感染在CREB和CAMKIIA的伴随下调以及已知可以调节突触可塑性的其他17个基因上上调HDAC2表达。此外，我们首次表明可卡因显着上调HDAC2基因表达并下调miR-155，并用miR-155转染可显着抑制HIV感染。因此，我们假设可卡因通过调节CNS细胞中的HDAC2表达，从而导致调节神经元活性和突触可塑性的基因的转录基因的转录抑制，从而起作用HIV感染的神经病发生。具体目标是确定：1​​）与HIV-1病毒相关的可卡因是否调节HDAC2是否会在原代人小胶质细胞中负面调节突触可塑性/记忆基因，海马神经元和星形胶质细胞，从而有助于手的进展； 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手的治疗策略。因此，对可卡因和与HIV相关的表观遗传学变化的理解及其在神经病发生中的影响将对HIV感染的可卡因使用者的治疗性靶向和控制具有翻译意义。