Cyclin requirements in gammaherpesvirus infection and disease

伽马疱疹病毒感染和疾病中的细胞周期素需求

基本信息

批准号：
8685199
负责人：
Linda F. Van Dyk
金额：
$ 29.89万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685199
关键词：
Animals Biochemical Biochemistry Biological Assay Burkitt Lymphoma Bypass CDK6-associated protein p18 Cancer Biology Cell Cycle Cell Cycle Inhibition Cell Proliferation Cells Chronic Chronic Disease Cyclin A Cyclin E Cyclins Development Disease Genes Genetic Grant Herpesviridae Hodgkin Disease Homologous Gene Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immunocompetent Immunologic Deficiency Syndromes Immunosuppression In Vitro Individual Infection Inflammatory Integration Host Factors Intervention Investigation Kaposi Sarcoma Knowledge Lymphoma Lymphoproliferative Disorders Malignant Neoplasms Mediating Modeling Molecular Mus Nasopharynx Carcinoma Outcome Pathogenesis Pathology Pathway interactions Peritoneal Fluid Phase Phosphotransferases Process Property Recombinants Reporting Risk Factors Role Satellite Viruses Shapes Specificity Staging Testing Therapeutic Transplantation Tumor Suppressor Proteins Viral Viral Genes Virus Virus Diseases Work cellular targeting cyclin D3 gammaherpesvirus gene function genetic analysis in vivo in vivo Model inhibitor/antagonist insight kinase inhibitor mouse model pathogen protein protein interaction reactivation from latency recombinant virus tumorigenesis viral cyclin

项目摘要

DESCRIPTION (provided by applicant): Gammaherpesviruses result in lifelong infection associated with malignancies and other chronic disease in immune deficient individuals. The human gammaherpesviruses include Epstein Barr virus and Kaposi's Sarcoma associated virus, which are associated with Burkitt's lymphoma, Hodgkin's lymphoma, post-transplant lymphoproliferative disorder, nasopharyngeal carcinoma, peritoneal effusion lymphoma and Kaposi's sarcoma. Given the strict host specificity of the human gammaherpesviruses, a major challenge is to understand the host and viral factors that regulate the outcome of gammaherpesvirus infection in vivo, in both healthy and immune compromised individuals. This proposal makes extensive use of the mouse gammaherpesvirus 68, to investigate the genetic contribution of viral and host genes in shaping the outcome of infection. Through our previous work, we developed an extensive knowledge of the precise in vivo contexts in which a viral gene, the viral cyclin, promotes chronic infection. We identified seven different parameters of gammaherpesvirus infection and disease, including models of immune deficiency that are dependent on the virus encoded cyclin homolog. In this grant, we will dissect the molecular pathways used by the viral cyclin to promote infection in vivo, using recombinant viruses in which the viral cyclin has been replaced by alternate viral or cellular cyclins. We will characterize the viral cyclin activity in all cyclin dependent aspects of infection, identify the infected cell reservoir in presence and absence of the viral cyclin, and define the molecular mechanism of the viral cyclin in both persistent infection and reactivation from latency infection. These recombinant viruses reveal distinct, non-overlapping mechanisms of viral cyclin action. Moreover, since different cellular cyclins are able to substitute for distinct phases of the viral infection, comparing the biochemical properties of different cyclins in distinct contexts of infection will result in significant insights in gammaherpesvirus infection and disease. By integrating our unique in vivo insights into the viral cyclin with these recombinant viruses and our identification of the cellular target of the viral cyclin in virus reactivation, this grant wil combine biochemistry and genetics, with in vitro and in vivo models of infection to define new molecular pathways that promote gammaherpesvirus infection and pathogenesis in the whole animal. Further, we propose to test candidate inhibitors of viral cyclins and viral cyclin dependent functions both in vitro and in vivo. Finally, our demonstration that host cyclins can facilitate virus infection and that a specific host tumor suppressor can repress virus reactivation promises that our investigation of the virus encoded cyclins will advance the field of cancer biology beyond virus associated oncogenesis. These studies of the v-cyclin have, and will continue to yield fundamental insights into gammaherpesvirus infection and further elucidate new mechanisms by which gammaherpesvirus pathogenesis can be abrogated.

描述（由申请人提供）：伽玛疱疹病毒导致免疫缺陷个体中与恶性肿瘤和其他慢性疾病相关的终生感染。人类伽马疱疹病毒包括EB病毒和卡波西肉瘤相关病毒，它们与伯基特淋巴瘤、霍奇金淋巴瘤、移植后淋巴增殖性疾病、鼻咽癌、腹膜渗出性淋巴瘤和卡波西肉瘤有关。鉴于人类伽马疱疹病毒严格的宿主特异性，一个主要挑战是了解在健康和免疫受损个体中调节体内伽马疱疹病毒感染结果的宿主和病毒因素。该提案广泛利用小鼠伽马疱疹病毒 68 来研究病毒和宿主基因在影响感染结果中的遗传贡献。通过我们之前的工作，我们对病毒基因（病毒细胞周期蛋白）促进慢性感染的精确体内环境有了广泛的了解。我们确定了伽玛疱疹病毒感染和疾病的七个不同参数，包括依赖于病毒编码的细胞周期蛋白同源物的免疫缺陷模型。在这笔资助中，我们将使用重组病毒来剖析病毒细胞周期蛋白用于促进体内感染的分子途径，其中病毒细胞周期蛋白已被替代病毒或细胞细胞周期蛋白取代。我们将表征感染的所有细胞周期蛋白依赖性方面的病毒细胞周期蛋白活性，识别病毒细胞周期蛋白存在和不存在的受感染细胞储库，并定义病毒细胞周期蛋白在持续感染和潜伏感染重新激活中的分子机制。这些重组病毒揭示了病毒细胞周期蛋白作用的独特的、不重叠的机制。此外，由于不同的细胞周期蛋白能够替代病毒感染的不同阶段，因此比较不同感染背景下不同细胞周期蛋白的生化特性将有助于对伽玛疱疹病毒感染和疾病产生重要的见解。通过将我们对病毒细胞周期蛋白的独特体内见解与这些重组病毒相结合，以及我们对病毒再激活中病毒细胞周期蛋白的细胞靶标的识别，这笔资助将把生物化学和遗传学与体外和体内感染模型结合起来，以定义新的病毒细胞周期蛋白。促进整个动物伽马疱疹病毒感染和发病机制的分子途径。此外，我们建议在体外和体内测试病毒细胞周期蛋白和病毒细胞周期蛋白依赖性功能的候选抑制剂。最后，我们证明宿主细胞周期蛋白可以促进病毒感染，并且特定的宿主肿瘤抑制因子可以抑制病毒重新激活承诺我们对病毒编码的细胞周期蛋白的研究将推动癌症生物学领域超越病毒相关的肿瘤发生。这些对 v-细胞周期蛋白的研究已经并将继续对伽马疱疹病毒感染产生基本见解，并进一步阐明可以消除伽马疱疹病毒发病机制的新机制。