权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.