Core Director: Hye-Ra-Lee

核心导演：李惠拉

• 批准号: 9323342
• 负责人: Jae U Jung
• 金额: $ 14.05万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323342
• 关键词: Address; Africa; Area; Artificial Chromosomes; Bacteria; Cancer Etiology; Cell Culture System; Cell model; Cessation of life; Cultured Cells; Development; Disease; Generations; Genes; Genome; Goals; Health; Herpesviridae Infections; Human; Human Herpesvirus 8; In Vitro; Individual; Infection; Kaposi Sarcoma; Low Prevalence; Malignant Neoplasms; Mediating; Mesenchymal Stem Cells; Molecular Biology; Multicentric Angiofollicular Lymphoid Hyperplasia; Mutagenesis; Mutation; Oncogenic; Pathogenesis; Pathway interactions; Rattus; Reagent; Reporting; Services; System; Technology; Therapeutic; Vaccines; Viral; Viral Genes; Viral Genome; Viral Pathogenesis; Virus; experimental study; gammaherpesvirus; gene function; in vivo; insight; mutant; overexpression; pathogen; primary effusion lymphoma; tumor; tumorigenesis; virology; virus host interaction

Kaposi's sarcoma-associated herpesvirus (KSHV) has been consistently identified in Kaposi's sarcoma (KS) tumors, primary effusion lymphoma (PEL), and Multicentric Castleman's disease. Although classical KS has a low prevalence rate worldwide, the more aggressive endemic KS, seen primarily in Africa, accounts for nearly half of the reported cancers in some regions and is the leading cause of cancer death in those areas. Despite being a pressing human health problem, there has been almost no attempt so far to develop protective and/ or therapeutic reagents against KSHV infection and its associated diseases. In addition, a majority of KSHV studies have been restricted to the overexpression system of the selected viral genes in the absence of viral complete genome and infection, leading to limited understanding of KSHV persistence and pathogenesis that are essential in developing safe and effective anti-viral agents and vaccines against this oncogenic pathogen. The major goal of our virology core is to provide supports and service for system to address these fundamental issues through KSHV BAC mutagenesis and primary rat mesenchymal stem cells (MSC) models. The efficient generation of mutants of KSHV using bacteria artificial chromosome (BAC) technology would significantly contribute to the understanding of viral gene functions in virus-host interaction. Furthermore, with KSHV, tumors usually develop long after the initial infection in very small percentage of infected hosts, indicating that cooperation with cellular genetic changes is required for the development of tumors. Our MSC models thus will be used to delineate viral genes and cellular pathways that mediate KSHV oncogenesis. Moreover, the mechanism by which gammaherpesviruses establish persistent infection in vivo and cause diseases is not understood. Experiments with individual viral genes in cultured cells have provided essential information about their possible function(s). While experiments in vitro may provide important clues as to their function(s), they cannot demonstrate how these genes contribute to pathogenesis in the complicated host system in vivo, because the network of indirect and multiple interactions during infection in vivo cannot be effectively defined in cell culture systems. Additionally, tumors usually develop long after the initial infection in a very small percentage of infected hosts, indicating that cooperation with cellular genetic change(s) is required for the developments of tumors. Addressing these issues requires an experimental system in which the host and viral genomes can be manipulated and infections can be performed in controlled manner. Thus, our core will provide a combination of in vitro molecular biology aspect within a virus context via KSHV BAC mutagenesis and in vivo viral pathogenesis through primary rat mesenchymal stem cells models to get better insights into the mechanisms underlying infection and associated disease.

Kaposi的肉瘤相关疱疹病毒（KSHV）一直在Kaposi的肉瘤（KS）中始终鉴定 肿瘤，原发性积液淋巴瘤（PEL）和多中心Castleman病。虽然古典KS有一个 全世界低的患病率，主要在非洲的攻击性地方性KS，几乎占 在某些地区，有一半的癌症是这些地区癌症死亡的主要原因。尽管 作为一个紧迫的人类健康问题，到目前为止，几乎没有尝试开发保护性和/或 针对KSHV感染及其相关疾病的治疗试剂。此外，大多数KSHV 在没有病毒的情况下，研究仅限于所选病毒基因的过表达系统 完全基因组和感染，导致对KSHV持久性和发病机理的了解有限 针对这种致癌病原体开发安全有效的抗病毒剂和疫苗至关重要。 我们病毒学核心的主要目标是为系统提供支持和服务，以解决这些基本 通过KSHV BAC诱变和原发性大鼠间充质干细胞（MSC）模型的问题。高效 使用人工染色体（BAC）技术生成KSHV突变体的生成 有助于理解病毒基因在病毒宿主相互作用中的功能。此外，与KSHV一起 肿瘤通常在初次感染后很长一段时间内发育很长一部分，而感染的宿主则表明 肿瘤发展需要与细胞遗传变化的合作。因此，我们的MSC模型将 用于描绘介导KSHV肿瘤发生的病毒基因和细胞途径。 此外，γ掌病毒在体内建立持续感染的机制并引起 疾病尚不理解。在培养细胞中使用单个病毒基因的实验提供了必不可少的 有关其可能功能的信息。尽管体外实验可能会提供有关其的重要线索 功能，他们无法证明这些基因在复杂宿主中如何促进发病机理 体内系统，因为在体内感染过程中间接和多个相互作用网络不能是 在细胞培养系统中有效定义。此外，肿瘤通常在初次感染后很长一段 受感染的宿主的比例很小，表明与细胞遗传变化的合作是 肿瘤发展所必需的。解决这些问题需要一个实验系统 可以操纵宿主和病毒基因组，并可以以受控的方式进行感染。因此， 我们的核心将通过KSHV BAC在病毒环境中提供体外分子生物学方面的结合 通过原代大鼠间充质干细胞模型的诱变和体内病毒发病机制变得更好 洞悉感染和相关疾病的机制。