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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.