Cocaine in the Neuropathogenesis of HIV infection: Role of HDAC2

描述（由申请人提供）：COST是感染HIV-1并随后发展为艾滋病的重要风险因素。这项拟议的研究旨在剖析可卡因和艾滋病毒相关的表观遗传机制在艾滋病毒相关的神经认知障碍（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HDAC 2，因为已知它通过调节树突棘的密度和影响成熟神经元中的突触传递在认知功能中发挥关键作用。然而，HDAC 2在HAND发展中的作用在可卡因的背景下尚未阐明。在我们已发表的和初步的研究中，我们发现HIV-1达特蛋白和HIV-1感染上调HDAC 2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著上调HDAC 2基因表达并下调miR-155，并且转染miR-155显著抑制HIV感染。因此，我们假设可卡因通过调节CNS细胞中HDAC 2的表达，导致调节神经元活性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起辅助因子的作用。具体目标是确定：1）可卡因与HIV-1病毒联合是否调节HDAC 2，HDAC 2反过来负调节原代人小胶质细胞、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）HDAC 2的抑制是否逆转可卡因和HIV-1病毒对神经元可塑性基因和树突棘密度的影响，以及3）可以探索使用转铁蛋白偶联的脂质体纳米制剂递送HDAC 2特异性siRNA和miR-155穿过体外血脑屏障（BBB）模型和在HIV-E SCID可卡因小鼠模型中作为HAND的治疗策略。因此，理解可卡因和HIV相关的表观遗传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中HAND的治疗靶向和控制具有转化意义。

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.