Epigenetic Regulation of HSV Infection of Oral Cells

口腔细胞 HSV 感染的表观遗传调控

• 批准号: 8730750
• 负责人: DAVID M. KNIPE
• 金额: $ 41.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-21 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730750
• 关键词: Anti-Retroviral Agents; Antiviral Agents; Antiviral Therapy; Cell Nucleus; Cells; Chromatin; DNA; Disease; Drug Targeting; Epigenetic Process; Epithelial Cells; Euchromatin; Gene Expression; Genes; Genome; HIV; HIV Infections; HIV Protease Inhibitors; Herpesvirus 1; Heterochromatin; Human; IRF3 gene; Individual; Infection; Interferons; Kinetics; Lead; Lytic; Lytic Phase; Malignant Neoplasms; Mouth Diseases; Mouth Neoplasms; Neurons; Nuclear; Oncogenic; Oral; Oral cavity; Pharmaceutical Preparations; Process; Regulation; Role; Signal Pathway; Signal Transduction; Simplexvirus; System; Testing; Viral; Viral Genes; Virus Diseases; cell type; in vivo; keratinocyte; latent infection; malignant mouth neoplasm; neoplastic cell; novel; oral infection; osteosarcoma; public health relevance; response; sensor; viral DNA

DESCRIPTION (provided by applicant): Epigenetic mechanisms control many normal and diseased state processes. In this proposal we will use herpes simplex virus 1 (HSV-1) as a probe of the epigenetic mechanisms operative in normal and diseased oral epithelial cells. Our specific aims are: 1. To define the mechanisms of epigenetic regulation of HSV-1 gene expression in normal oral keratinocytes. We will first define the baseline mechanisms of epigenetic regulation of HSV gene expression in immortalized normal human oral keratinocytes (NOK cells), define the kinetics of chromatin and heterochromatin association with viral lytic genes in oral keratinocytes, define the host chromatin factors that positively and negatively regulate viral gene expression in NOK cells, and test the ability of drugs that target chromatin factors to synergize with traditional herpesviral drugs. 2. Test the hypothesis that HSV-1 infection can be used as a probe of epigenetic mechanisms in different oral disease states. Epigenetic mechanisms are altered in HIV-infected oral epithelial cells, in anti-retroviral treated cells, and in tumor cells. We have found that HSV-1 infection can be used as a probe of osteosarcoma cells to identify novel epigenetic mechanisms that are operative in these cells. Therefore, we will test if HSV-1 infection can identify altered epigenetic mechanisms in diseased oral cells. In this Aim we will define the epigenetic mechanisms in oral epithelial cells from HIV+/anti-retroviral treated individuals versus HIV- individuals and in oral epithelial cells treatd with HIV protease inhibitors, and define the epigenetic mechanisms operative in oral tumor cells. 3. To define the effect of oral disease states on IFI16 nuclear sensing of HSV DNA. We have shown that in normal human cells including oral keratinocytes that the nuclear IFI16 DNA sensor is required for induction of IFN-¿ and interferon-stimulated genes and for host silencing of HSV IE. In this Aim we will determine if IFI16 sensing of HSV DNA is altered in oral keratinocytes from HIV+/anti-retroviral treated individuals versus HIV- individuals, and in oral epithelial cells treated with HIV protease inhibitors. In this aim we will determine if IFI16 sensig of HSV-1 DNA is altered in oral tumor cells. These studies on epigenetic regulation of HSV-1 gene expression have the potential of defining new mechanisms of viral infection and disease in oral epithelial cells and new antiviral strategies. Furthermore, the studies will provide new mechanisms for identifying oncogenic mechanisms and therapies for oral cancers.

描述（由申请人提供）：表观遗传机制控制许多正常和疾病状态过程。在这个建议中，我们将使用单纯疱疹病毒1（HSV-1）作为探针的表观遗传机制在正常和患病的口腔上皮细胞。我们的具体目标是：1.目的探讨HSV-1基因在正常口腔黏膜角质形成细胞中表达的表观遗传学调控机制。我们将首先确定在永生化的正常人口腔角质形成细胞中HSV基因表达的表观遗传调控的基本机制（NOK细胞），定义了口腔角质形成细胞中染色质和异染色质与病毒裂解基因结合的动力学，定义了在NOK细胞中正向和负向调节病毒基因表达的宿主染色质因子，并测试针对染色质因子的药物与传统疱疹病毒药物协同作用的能力。2.测试HSV-1感染可用作不同口腔疾病状态下表观遗传机制的探针的假设。在HIV感染的口腔上皮细胞中，抗逆转录病毒治疗的 细胞和肿瘤细胞中。我们发现HSV-1感染可以作为骨肉瘤细胞的探针，以确定在这些细胞中有效的新的表观遗传机制。因此，我们将测试HSV-1感染是否可以识别患病口腔细胞中改变的表观遗传机制。在这个目标中，我们将定义在口腔上皮细胞中的表观遗传机制，从HIV+/抗逆转录病毒治疗的个体与HIV-个体，并在口腔上皮细胞用HIV蛋白酶抑制剂治疗，并定义在口腔肿瘤细胞中的表观遗传机制。3.确定口腔疾病状态对HSV DNA的IFI 16核感应的影响。我们已经证明，在包括口腔角质形成细胞在内的正常人类细胞中，细胞核IFI 16 DNA传感器是诱导IFN-γ和干扰素刺激基因以及宿主沉默HSV IE所必需的。在这个目标中，我们将确定是否IFI 16感应HSV DNA在口腔角质形成细胞从HIV+/抗逆转录病毒治疗的个人与HIV-的个人，并在口腔上皮细胞与HIV蛋白酶抑制剂治疗改变。在这个目标中，我们将确定在口腔肿瘤细胞中HSV-1 DNA的IFI 16敏感性是否改变。 这些关于HSV-1基因表达的表观遗传调控的研究有可能确定口腔上皮细胞中病毒感染和疾病的新机制以及新的抗病毒策略。此外，这些研究将为确定口腔癌的致癌机制和治疗提供新的机制。