Targeting KSHV malignancies and persistent infection

针对 KSHV 恶性肿瘤和持续感染

基本信息

批准号：
8943348
负责人：
Shou-Jiang Gao
金额：
$ 37.72万
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：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8943348
关键词：
Address Africa African Amides Animal Model Antineoplastic Agents Antiviral Agents Cell Death Cell Survival Cell physiology Cells Chromatin County Disease EZH2 gene Eastern Europe Epigenetic Process Fluorescent in Situ Hybridization Gene Expression Growth HIV Herpesviridae Herpesviridae Infections Histones Human Human Herpesvirus 8 IL2RA gene Immunocompetent Immunocompromised Host Individual Infection Integration Host Factors Kaposi Sarcoma Life MAPK14 gene Malignant Neoplasms Mediating Methods Modeling Modification Multicentric Angiofollicular Lymphoid Hyperplasia Mus Niacinamide Oncogenic Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Prevalence Proteins Role Sirtuins Small Interfering RNA System Testing Therapeutic Therapeutic Intervention Toxic effect Vaccines Viral Cancer Viral Pathogenesis Virus Virus Diseases Virus Inhibitors addiction anti-cancer therapeutic antiretroviral therapy base cell growth cell transformation cellular targeting combat cytotoxicity inhibitor/antagonist innovative technologies insight interest knock-down metaplastic cell transformation novel novel therapeutic intervention primary effusion lymphoma public health relevance screening single molecule sirtinol therapeutic target tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several cancers including Kaposi's sarcoma (KS) and primary effusion lymphoma frequently found in immunocompromised patients. Despite antiretroviral therapy, KS remains common among HIV-infected patients. Existing anti-herpesviral drugs and anticancer therapeutic methods are ineffective for treating KSHV-induced cancers. KSHV infection is for life- long, however, there is no vaccine for KSHV and no method for clearing KSHV persistent infection. Despite intensive studies, the critical host factors required for KSHV-induced cancers and KSHV persistent infection remain unclear mainly because of the lack of appropriate experimental system. Our team has developed two novel systems for (a) KSHV-induced cell growth transformation and tumorigenesis, and (b) KSHV persistent infection in NOD/SCID IL2R-/- (NSG) "humanized" mice. Using these novel systems, our studies have revealed KSHV extensive reprograming of cellular chromatins and gene expression networks, and identified several cellular pathways that are required for the growth and survival of KSHV latent/transformed cells. In particular, inhibitors of class III histone deacetylases (sirtuins) inuce massive cell death of KSHV-transformed cells but have minimal cytotoxicity to uninfected cells. The objective of this project is to identify and validate host factors and inhibitors targeting individual or combined cellular pathways that are essential for KSHV oncogenesis and persistent infection. Our hypothesis is that KSHV hijacks specific cellular pathways to promote cell growth and survival, and therefore therapeutic targeting of these pathways is effective for KSHV oncogenesis and persistent infection. We plan to accomplish the objective by delineating host factors and validating inhibitors targeting individual or combined cellular functions that are essential for KSHV oncogenesis and persistent infection (Aim 1); determining the mechanism by which sirtuins mediate the survival of KSHV- transformed cells (Aim 2); and examining the effects of targeting sirtuins on KSHV oncogenesis and persistent infection in animal models (Aim 3). In addition to the novel animal models, we will apply several innovative technologies such as single-molecule fluorescent in situ hybridization (SMFISH) to accomplish these aims. The proposed project is highly significant because it will identify therapeutic cellular targets an their inhibitors for viral persistent infections and pathogenesis. The results will provide insight into the mechanisms of KSHV- induced oncogenic addiction and persistent infection. The outcomes could also be applied to other virus- induced cancers and persistent viral infections.

描述（由申请人提供）：卡波西肉瘤相关疱疹病毒（KSHV）与多种癌症相关，包括卡波西肉瘤（KS）和常见于免疫功能低下患者的原发性渗出性淋巴瘤，尽管进行了抗逆转录病毒治疗，但卡波西肉瘤在艾滋病毒感染者中仍然很常见。抗疱疹病毒药物和抗癌治疗方法对治疗 KSHV 感染引起的癌症无效。然而，目前还没有针对 KSHV 的疫苗，也没有清除 KSHV 持续感染的方法，尽管进行了大量研究，但 KSHV 诱发癌症和 KSHV 持续感染所需的关键宿主因素仍不清楚，主要是因为缺乏适当的实验。我们的团队开发了两种新颖的系统，用于（a）KSHV诱导的细胞生长转化和肿瘤发生，以及（b）KSHV在NOD/SCID IL2R-/-（NSG）“人源化”中的持续感染。使用这些新系统，我们的研究揭示了 KSHV 对细胞染色质和基因表达网络的广泛重编程，并确定了 KSHV 潜伏/转化细胞生长和存活所需的几种细胞途径，特别是 III 类组蛋白的抑制剂。去乙酰酶（sirtuins）会导致 KSHV 转化细胞大量死亡，但对未感染细胞的细胞毒性极小。该项目的目的是鉴定和验证宿主因子和抑制剂。靶向对 KSHV 肿瘤发生和持续性感染至关重要的单个或组合细胞途径。我们的假设是，KSHV 劫持特定细胞途径以促进细胞生长和存活，因此我们计划针对这些途径进行治疗对 KSHV 肿瘤发生和持续性感染有效。通过描述宿主因素并验证针对单个或组合细胞功能的抑制剂来实现目标对 KSHV 肿瘤发生和持续感染至关重要（目标 1）；确定 Sirtuins 介导 KSHV 转化细胞存活的机制（目标 2）；并在动物模型中检查靶向 Sirtuins 对 KSHV 肿瘤发生和持续感染的影响（目标 3）除了新颖的动物模型之外，我们还将应用单分子荧光原位杂交（SMFISH）等多种创新技术来实现这些目标。研究结果将有助于深入了解 KSHV 诱导的致癌成瘾和持续性感染的机制。这些结果也可应用于其他病毒引起的癌症和持续性病毒感染。