Targeting KSHV malignancies and persistent infection

针对 KSHV 恶性肿瘤和持续感染

• 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
• 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

 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（由适用提供）：Kaposi与肉瘤相关的疱疹病毒（KSHV）与几种癌症有关，包括Kaposi的肉瘤（KS）和原发性积液淋巴瘤，在免疫强化患者中经常发现。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。现有的抗赫普病毒药物和抗癌治疗方法无效地治疗KSHV诱导的癌症。 KSHV感染是针对终身的，但是，KSHV没有疫苗，也没有清除KSHV持续感染的方法。尽管进行了深入的研究，但KSHV引起的癌症和KSHV持续感染所需的关键宿主因素仍然不清楚，这主要是由于缺乏适当的实验系统。我们的团队开发了两个新型系统，用于（a）KSHV诱导的细胞生长转化和肿瘤发生，（b）在点头/scIDIL2R-/ - （NSG）“人源化”小鼠中的KSHV持续感染。使用这些新型系统，我们的研究揭示了KSHV的细胞染色蛋白和基因表达网络的广泛重编程，并确定了KSHV潜在/转化细胞生长和存活所需的几种细胞途径。特别是，III类组蛋白脱乙酰基酶（Sirtuins）的抑制剂造成了KSHV转换细胞的大量细胞死亡，但对未感染的细胞具有最小的细胞毒性。该项目的目的是识别和验证靶向单个或组合细胞途径的宿主因素和抑制剂，这对于KSHV肿瘤发生和持续感染至关重要。我们的假设是，KSHV劫持了特定的细胞途径来促进细胞生长和存活，因此这些途径的热靶向对KSHV的肿瘤发生和持续感染有效。我们计划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 KSHV肿瘤发生和持续感染所必需的（AIM 1）；确定sirtuins中位数的机制，即KSHV转化的细胞的存活率（AIM 2）；并检查靶向Sirtuins对动物模型中KSHV肿瘤发生和持续感染的影响（AIM 3）。除了新型的动物模型外，我们还将应用几种创新技术，例如单分子荧光原位杂交（Smfish）来实现这些目标。拟议的项目非常重要，因为它将确定其抑制剂的治疗性细胞靶标的病毒持续感染和发病机理。结果将洞悉KSHV诱导的致癌成瘾和持续感染的机制。结果也可以应用于其他病毒引起的癌症和持续性病毒感染。