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（由适用提供）：Kaposi的肉瘤（KS）是与Kaposi肉瘤相关的疱疹病毒（KSHV）与感染相关的艾滋病患者中最常见的癌症。 KS通常与口腔有关，口服KSHV感染对于口服KS和病毒扩散是必要的。尽管抗逆转录病毒疗法，但KS在HIV感染的患者中仍然很常见。现有的抗病毒和抗癌疗法我们开发了三个新的系统来解决这些挑战：1）KSHV诱导的长期持续感染和KS发育的细胞转化，鉴定KSHV潜在感染所必需的因素可以导致开发针对口服KSHV持久感染和恶化的新型治疗方法。原发性人骨髓间充质干细胞（MSC），2）在点头/SCIDIL2R-/ - （NSG）“人性化”小鼠中口腔中的KSHV持续感染，而3）KSHV持续感染的原代人口腔上皮细胞中的原发性人性化细胞，Gingiva Mscs和Gingiva Mscs和Gingiva Mscs和牙科孔。使用这些模型，我们发现了潜在KSHV感染细胞中细胞染色蛋白和基因表达网络的广泛表观遗传重编程。此外，我们已经确定了包括Polycomb反射复合物2（PRC2）蛋白和III类组蛋白脱乙酰基酶Sirtuins在内的组蛋白修饰剂是潜在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诱导了包括KSHV转换细胞在内的潜在KSHV感染细胞的大规模细胞死亡，但对未感染的细胞具有最小的细胞毒性。基于这些结果，我们的假设是组蛋白修饰剂介导了潜在KSHV感染的口腔细胞的存活，因此抑制这些靶标可以杀死潜在的KSHV感染的细胞，从而有效地治疗性KSHV持续性感染和KSHV诱导的癌症。我们建议鉴定口腔细胞中KSHV潜在感染必不可少的组蛋白修饰剂（AIM 1）；描述组蛋白修饰剂介导潜在KSHV感染口腔细胞的存活的机制（AIM 2）；在治疗上清除口服KSHV持续感染，并通过靶向特定的组蛋白修饰剂来抑制动物模型中KSHV诱导的口腔癌（AIM 3）。该提出的项目很重要，因为它将描绘出口服KSHV持续感染和发病机理的必需组蛋白修饰剂，并确定有效的抑制剂，以抑制这些新靶标的治疗性抑制。结果将提供洞察力的洞察力机制，其机制持续感染和KSHV诱导的肿瘤发生。结局也可以应用于其他口腔持续性病毒感染和病毒诱导的癌症。