Molecular Basis of KSHV oncogenesis

 描述(申请人提供)：尽管20世纪医学研究和治疗取得了显著进步，但与感染相关的癌症仍然是全球主要的死亡原因之一。在使病原体入侵宿主种群并导致疾病的各种因素中，免疫抑制等宿主特征是最主要的促成因素。具体地说，与普通人群相比，艾滋病毒/艾滋病患者的卡波西氏肉瘤(KS)发病率更高，这突显了宿主免疫在控制卡波西肉瘤相关疱疹病毒(KSHV)方面的重要性，KSHV是七种人类肿瘤病毒之一。为了提高免疫抑制患者对KS的反应能力，我们应该更好地了解宿主和KS致病菌之间是如何相互作用的，以及KS致病菌如何在免疫低下的宿主中发挥作用。具体地说，要了解KSHV基因产物如何有助于持续感染和致病机制的建立，需要一种反向遗传学方法来进行病毒遗传操作，建立体外和体内的病毒致癌检测系统，以及在主动宿主免疫条件下建立体内病毒持续的动物模型。因此，我们在以下方面的研究成果将为KSHV体内持久性和致病机制的研究提供生物学基础：了解病毒逃避宿主免疫和细胞生长转化的病毒策略，建立具有感染性的KSHV BAC克隆和人源化的小鼠和灵长类动物模型。

 DESCRIPTION (provided by applicant): Despite remarkable advances in medical research and treatments during the 20th century, infection- associated cancers remain among the leading causes of death worldwide. Among a wide variety of factors that enable pathogens to invade host populations and cause diseases, host characteristics such as immunosuppression are the foremost contributing factors. Specifically, those with HIV/AIDS have an increased incidence of Kaposi's Sarcoma (KS) relative to the general population, highlighting how important host immunity is in controlling Kaposi's sarcoma-associated herpesvirus (KSHV) that is one of seven human oncoviruses. In order to improve our ability to respond more effectively to KS in immunosuppressed patients, we should thus improve our understanding of how hosts and KS-causing pathogen combat each other and how KS-causing pathogen operates in the immune compromised hosts. Specifically, understanding how KSHV gene products contribute to the establishment of persistent infection and pathogenesis requires a reverse genetics approach for the viral genetic manipulation, in vitro and in vivo assay systems for viral oncogenesis, and an animal model for in vivo viral persistence under active host immune conditions. Thus, our achievements in the following ways will provide biologically relevant settings for the study of in vivo KSHV persistence and pathogenesis: understanding the viral evasion of host immunity and the viral strategy of cell growth transformation and developing the infectious KSHV BAC clone and the humanized mouse and primate models.