HISTONE MODIFIERS IN ORAL KSHV INFECTION AND MALIGNANCIES

口腔 KSHV 感染和恶性肿瘤中的组蛋白修饰剂

基本信息

批准号：
9257374
负责人：
Shou-Jiang Gao
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-10 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257374
关键词：
Acquired Immunodeficiency Syndrome Address Animal Model Antineoplastic Agents Antiviral Agents Antiviral Therapy Bone Marrow CRISPR/Cas technology Cell Death Cell Survival Cells Chromatin Complex Dental Pulp Development Disease EZH2 gene Ephrin-B2 Epigenetic Process Epithelial Cells FOXO1A gene Gene Expression Gingiva HIV Herpesviridae Herpesviridae Infections Herpesvirus Vaccines Histone Deacetylase Histones Human Human Herpesvirus 8 IL2RA gene In Vitro Infection Kaposi Sarcoma Knock-out Lead Life Malignant Neoplasms Mediating Mesenchymal Stem Cells Modeling Modification Oral Oral Manifestations Oral cavity Outcome Palate Kaposi&apos s Sarcoma Pathogenesis Pathology Pathway interactions Patients Polycomb Proteins Regulation Role Sirtuins System TP53 gene Technology Therapeutic Therapeutic Intervention Treatment Efficacy Tumor Stem Cells Vaccines Viral Viral Cancer Virus Virus Diseases antiretroviral therapy base cancer therapy cell transformation cytotoxicity humanized mouse in vivo ineffective therapies inhibitor/antagonist innovation insight killings knock-down latent infection malignant mouth neoplasm metaplastic cell transformation novel novel therapeutic intervention oral infection public health relevance small hairpin RNA therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Kaposi's sarcoma (KS) is the most common cancer in AIDS patients associated with infection by Kaposi's sarcoma-associated herpesvirus (KSHV). KS is often involved with oral cavity, and oral KSHV infection is necessary for the development of oral KS and virus spread. Despite antiretroviral therapy, KS remains common among HIV-infected patients. Existing antiviral and anticancer therapies are ineffective for eliminating persistent KSHV infection and for treating KSHV-induced cancer. Because KSHV latent infection is necessary for its long-term persistent infection and for KS development, identificatio of factors essential for KSHV latent infection can lead to the development of novel therapeutic approaches for oral KSHV persistent infection and malignancies. We have developed three novel systems to address these challenges: 1) KSHV-induced cellular transformation of primary human bone marrow mesenchymal stem cells (MSCs), 2) KSHV persistent infection in the oral cavity in NOD/SCID IL2R-/- (NSG) "humanized" mice, and 3) KSHV persistent infection in primary human oral epithelial cells, gingiva MSCs and dental pulp MSCs. Using these models, we have found extensive epigenetic reprograming of cellular chromatins and gene expression networks in latent KSHV- infected cells. Furthermore, we have identified histone modifiers including polycomb repressive complex 2 (PRC2) proteins and class III histone deacetylases sirtuins as the critical factors for the survival of latent KSHV-infected cells. Significantly, targeting PRC2 proteins and sirtuins induce massive cell death of latent KSHV-infected cells including KSHV-transformed cells but have minimal cytotoxicity to uninfected cells. Based on these results, our hypothesis is that histone modifiers mediate the survival of latent KSHV-infected oral cells, and therefore inhibition of these targets can kill latent KSHV-infected cells resulting in effective therapeutic intervention for oral KSHV persistent infection and KSHV-induced cancer. We propose to identify the histone modifiers essential for KSHV latent infection in oral cells (Aim 1); delineate the mechanisms by which histone modifiers mediate the survival of latent KSHV infected oral cells (Aim 2); and therapeutically clear oral KSHV persistent infection and inhibit KSHV-induced oral cancer in animal models by targeting specific histone modifiers (Aim 3). The proposed project is significant because it will delineate the essential histone modifiers for oral KSHV persistent infection and pathogenesis, and identify effective inhibitors for therapeutic inhibition of these novel targets. The results will provide insights int the mechanisms of oral KSHV persistent infection and KSHV-induced oncogenesis. The outcomes can also be applied to other oral persistent viral infections and virus-induced cancer.

描述（申请人提供）：卡波西肉瘤（KS）是艾滋病患者中最常见的癌症，与卡波西肉瘤相关疱疹病毒（KSHV）感染相关，KS通常累及口腔，口腔KSHV感染是其发生的必要条件。尽管有抗逆转录病毒治疗，但 KS 在 HIV 感染者中仍然很常见，现有的抗病毒和抗癌疗法对治疗无效。消除持续性 KSHV 感染和治疗 KSHV 诱发的癌症由于 KSHV 潜伏感染对于其长期持续感染和 KS 发展是必要的，因此识别 KSHV 潜伏感染所必需的因素可以导致开发新的口服 KSHV 治疗方法。我们开发了三种新系统来应对这些挑战：1）KSHV 诱导的原代人骨髓间充质干细胞（MSC）的细胞转化，2）KSHV 持续性。 NOD/SCID IL2R-/- (NSG)“人源化”小鼠的口腔感染，以及 3) 原代人口腔上皮细胞、牙龈 MSC 和牙髓 MSC 中的 KSHV 持续感染。使用这些模型，我们发现了广泛的感染。潜伏 KSHV 感染细胞中细胞染色质和基因表达网络的表观遗传重编程。此外，我们还鉴定了组蛋白修饰剂，包括多梳抑制复合物 2 (PRC2) 蛋白和 III 类组蛋白脱乙酰酶 Sirtuins 是潜伏 KSHV 感染细胞存活的关键因素。值得注意的是，靶向 PRC2 蛋白和 Sirtuins 会诱导潜伏 KSHV 感染细胞（包括 KSHV 转化细胞）大量细胞死亡，但细胞毒性极小。基于这些结果，我们的假设是组蛋白修饰剂介导潜伏 KSHV 感染的口腔细胞的存活。因此，抑制这些靶标可以杀死潜伏的 KSHV 感染细胞，从而对口腔 KSHV 持续感染和 KSHV 诱导的癌症进行有效的治疗干预。我们建议鉴定口腔细胞中 KSHV 潜伏感染所必需的组蛋白修饰剂（目标 1）。描述组蛋白修饰剂介导潜伏 KSHV 感染的口腔细胞存活的机制（目标 2），并治疗性清除口腔 KSHV 持续感染并抑制 KSHV 诱导的口腔细胞；通过针对特定组蛋白修饰剂在动物模型中研究癌症（目标 3），该项目意义重大，因为它将描述口腔 KSHV 持续感染和发病机制的基本组蛋白修饰剂，并确定用于治疗性抑制这些新靶标的有效抑制剂。提供了对口腔 KSHV 持续感染和 KSHV 诱导的肿瘤发生机制的见解，其结果也可应用于其他口腔持续病毒感染和病毒诱发的癌症。