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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：
8329877
负责人：
Linda F. Van Dyk
金额：
$ 30.63万
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/8329877
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. PUBLIC HEALTH RELEVANCE: The cellular cyclins have been strongly associated with tumorigenesis since their discovery, and while they were initially considered exclusively for regulating cell proliferation, recent studies show that frequent overlap in the cell proliferation functions, yet that their roles in cell fate, development and differentiation are distinct. Our studies of the virus encoded cyclins have identified that these cyclins are required at several stages of infection and pathogenesis, and that they work by at least two different mechanisms and that one of these mechanisms functions to oppose the activity of a cellular tumor suppressor protein. The work proposed here will define the mechanism of the viral cyclins during authentic infection and disease and will identify potential interventions relevant to human inflammatory disease and malignancies, both those associated with gammaherpesvirus infection and related to cellular cyclins and tumor suppressors.

描述（由申请方提供）：γ疱疹病毒可导致免疫缺陷个体发生与恶性肿瘤和其他慢性疾病相关的终身感染。人类γ疱疹病毒包括爱泼斯坦巴尔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、移植后淋巴组织增生性疾病、鼻咽癌、腹膜渗出性淋巴瘤和卡波西肉瘤相关。鉴于人γ疱疹病毒严格的宿主特异性，一个主要的挑战是了解宿主和病毒因素，调节体内γ疱疹病毒感染的结果，在健康和免疫受损的个人。该提议广泛使用小鼠γ疱疹病毒68，以研究病毒和宿主基因在形成感染结果中的遗传贡献。通过我们以前的工作，我们开发了一个广泛的知识，精确的体内环境中的病毒基因，病毒细胞周期蛋白，促进慢性感染。我们确定了γ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。在这项研究中，我们将使用重组病毒，其中病毒细胞周期蛋白已被替代的病毒或细胞周期蛋白所取代，剖析病毒细胞周期蛋白用于促进体内感染的分子途径。我们将在所有依赖于细胞周期蛋白的感染方面表征病毒细胞周期蛋白的活性，鉴定存在和不存在病毒细胞周期蛋白的感染细胞库，并定义病毒细胞周期蛋白在持续感染和潜伏感染再激活中的分子机制。这些重组病毒揭示了不同的，非重叠的病毒细胞周期蛋白的作用机制。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，比较不同感染背景下不同细胞周期蛋白的生化特性将导致对γ疱疹病毒感染和疾病的重要见解。通过整合我们独特的在体内的见解病毒细胞周期蛋白与这些重组病毒和我们的病毒细胞周期蛋白在病毒再活化的细胞靶点的鉴定，该授权将结合联合收割机生物化学和遗传学，在体外和体内感染模型，以确定新的分子途径，促进γ疱疹病毒感染和发病机制，在整个动物。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，我们证明了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的再活化。我们对病毒编码的细胞周期蛋白的研究将使癌症生物学领域超越病毒相关的肿瘤发生。这些研究的v-细胞周期蛋白，并将继续产生根本的见解γ疱疹病毒感染，并进一步阐明新的机制，γ疱疹病毒的发病机制可以被废除。公共卫生关系：细胞周期蛋白自发现以来与肿瘤发生密切相关，虽然最初认为它们仅用于调节细胞增殖，但最近的研究表明，它们在细胞增殖功能中经常重叠，但它们在细胞命运，发育和分化中的作用是不同的。我们对病毒编码的细胞周期蛋白的研究已经确定，这些细胞周期蛋白在感染和发病的几个阶段是必需的，并且它们通过至少两种不同的机制起作用，并且这些机制之一的功能是对抗细胞肿瘤抑制蛋白的活性。本文提出的工作将定义病毒周期蛋白在真实感染和疾病过程中的机制，并将确定与人类炎症性疾病和恶性肿瘤相关的潜在干预措施，这些干预措施与γ疱疹病毒感染相关，与细胞周期蛋白和肿瘤抑制因子相关。