KSHV Persistence and Pathogenesis

KSHV 的持续性和发病机制

• 批准号: 9115068
• 负责人: Jae U Jung
• 金额: $ 147.22万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-13 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115068
• 关键词: AIDS/HIV problem; Address; Animal Model; Antiviral Agents; Applications Grants; Arts; Biological Assay; Cause of Death; Cells; Characteristics; Data; Development; Embryo; Future; General Population; Genetic; Genome; Goals; Growth; Health; Herpesviridae Infections; Host Defense; Human; Human Herpesvirus 8; Immune; Immune response; Immunity; Immunocompromised Host; Immunosuppression; In Vitro; Incidence; Infection; Invaded; Kaposi Sarcoma; Malignant Neoplasms; Mediating; Medical Research; Mesenchymal; Mesenchymal Stem Cells; Metabolic Control; MicroRNAs; Multicentric Angiofollicular Lymphoid Hyperplasia; Mutagenesis; Nucleotides; Nude Mice; Oncogenic; Organ Transplantation; Pathogenesis; Pathway interactions; Phosphotransferases; Population; Predisposing Factor; Principal Investigator; Production; Program Research Project Grants; Role; Scheme; Solid; System; Therapeutic Intervention; Vaccines; Viral; Viral Genes; Virus; combat; gene product; genetic approach; genetic manipulation; humanized mouse; improved; in vivo; insight; monocyte; mouse model; multidisciplinary; novel; nucleotide metabolism; overexpression; pathogen; primary effusion lymphoma; programs; protein function; reverse genetics; stem; tumor; tumorigenesis; vaccine development; virus genetics

Despite being a significant human health problem, 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 to in vivo KSHV persistence and pathogenesis that are essential in developing safe and effective anti-viral agents and vaccines against this oncogenic pathogen. Specifically, understanding how KSHV gene products contribute to the establishment of persistent infection and pathogenesis requires a reverse genetics approach for the viral genetic deficiencies, an in vitro and in vivo assay system for the viral oncogenesis, and an animal model for the in vivo viral persistence under active host immune conditions. Fortunately, our Program Project Grant (PPG) leaders have recently established a new "infectious" bacterial artificial clone (BACI6) of KSHV genome that significantly improves the efficiency of the genetic manipulation and virus production (Project 1), a novel system to investigate host's control of the KSHV nucleotide metabolism (Project 2), an efficient KSHV infection and transformation system using primary embryonic metanephric mesenchymal stem cells (MSC cells) (Project 3), and a well-controlled in vivo infection system using a humanized mouse model where KSHV establishes persistent infection and is disseminated into the B and monocyte lineages (Core). Thusly, this multi-disciplinary PPG application is directed toward investigating the host's tricks of Immune recognition and attack as well as the KSHV's tactics of immune evasion and pathogenesis by utilizing recently developed "infectious" KSHV genetic system, in vitro and in vivo transformation assays, and in vivo humanized mouse models. The major goal of this multi-project grant application is to address (1) how hosts have developed effective mechanisms necessary to control KSHV infection and replication, (2) how KSHV has evolved the various mechanisms necessary to thwart and exploit the host defenses, and (3) how KSHV has conferred the infected cells with oncogenic signatures. This application consists of three Projects with multidisciplinary focused schemes. In addition, the Cores provide an efficient genetic manipulation system for KSHV mutagenesis, a state-of-art humanized mouse model for KSHV persistence and a MSC cell/nude mouse system for KSHV oncogenesis and the Administrative Core provides the overall program milestone and data dissemination.

尽管是人类健康问题，但在没有病毒完全基因组和感染的情况下，大多数KSHV研究都仅限于所选病毒基因的过表达系统，从而导致对体内KSHV持久性和发病机理的了解有限，这对于开发安全有效的抗病毒药物和疫苗对这种负性致病性是至关重要的。具体而言，了解KSHV基因产品如何有助于建立持续性感染和发病机理，需要针对病毒遗传缺陷的反向遗传学方法，一种病毒性肿瘤发生的体外和体内测定系统，以及在主动免疫条件下体内病毒持久性的动物模型。 Fortunately, our Program Project Grant (PPG) leaders have recently established a new "infectious" bacterial artificial clone (BACI6) of KSHV genome that significantly improves the efficiency of the genetic manipulation and virus production (Project 1), a novel system to investigate host's control of the KSHV nucleotide metabolism (Project 2), an efficient KSHV infection and transformation system using primary embryonic metanephric间充质干细胞（MSC细胞）（项目3），以及使用人源化小鼠模型控制的体内感染系统，其中KSHV建立了持续的感染，并将其传播到B和单核细胞谱系中（核心）。因此，这种多学科的PPG应用是针对研究宿主的免疫识别和攻击的技巧，以及KSHV通过利用最近开发的“感染性” KSHV遗传系统，体外和体内转化和体内转化分析以及体内人性化的人类人体人体小鼠模型，通过使用最近开发的“感染性” KSHV遗传系统。该多项目赠款应用程序的主要目的是解决（1）宿主如何开发了控制KSHV感染和复制所需的有效机制，（2）KSHV如何发展如何挫败和利用宿主防御的各种机制，以及（3）如何将KSHV与Oncenogeninic Indecatientures授予感染细胞。该应用程序由三个具有多学科集中计划的项目组成。此外，核心为KSHV诱变提供了有效的遗传操纵系统，KSHV诱变是KSHV持久性的最先进的人源化小鼠模型，以及用于KSHV肿瘤发生的MSC细胞/裸小鼠系统，并且管理核心提供了整体程序Milestone和数据传播。