Cocaine in the Neuropathogenesis of HIV infection: Role of HDAC2

描述(由申请人提供)：可卡因是感染艾滋病毒-1并随后发展为艾滋病的一个重要风险因素。这项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和神经退行性疾病发展的重要调节机制。在目前的研究中，我们将重点关注HDAC2，因为众所周知，HDAC2通过调节树突棘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，HDAC2在手部发育中的作用还没有在可卡因的背景下阐明。在我们已发表的和初步的研究中，我们发现HIV-1 Tat蛋白和HIV-1感染上调了HDAC2的表达，同时下调了CREB和CamKIIa以及其他17个已知的调节突触可塑性的基因。此外，我们首次表明可卡因显着上调HDAC2基因的表达，下调miR-155的表达，并通过miR-155的转染显着抑制HIV感染。因此，我们假设可卡因通过调节中枢神经系统细胞中HDAC2的表达，导致调节神经元活动和突触可塑性的基因的转录抑制，在HIV感染的神经发病机制中发挥辅助作用。该研究的具体目标是确定：1)可卡因与艾滋病毒-1病毒联合应用是否能调节HDAC2基因，进而负面调控原代人类小胶质细胞、海马神经元和星形胶质细胞的突触可塑性/记忆基因，从而促进手部疾病的进展；2)抑制HDAC2是否能逆转可卡因和HIV-1病毒对神经元可塑性基因和树突棘密度的影响；3)通过体外血脑屏障模型和使用转铁蛋白偶联脂质体纳米制剂的HIV-E SCID可卡因小鼠模型，探讨能否将HDAC2特异性siRNA和miR-155靶向传递至血脑屏障(BBB)模型。因此，了解可卡因和HIV相关的表观遗传学变化及其在神经发病机制中的意义将对HIV感染的可卡因使用者的治疗靶向和手部控制具有翻译意义。

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.