Identification of a naturally occurring model for EBV-associated lymphomagenesis

EBV 相关淋巴瘤发生的自然模型的鉴定

• 批准号: 8244208
• 负责人: NICOLA J MASON
• 金额: $ 24万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8244208
• 关键词: Address; Animal Model; Antibodies; B-Cell Lymphomas; B-Lymphocytes; Biological Assay; Birds; Breeding; Burkitt Lymphoma; Canis familiaris; Capsid Proteins; Cell Culture Techniques; Chromosomal translocation; Chronic; Clinical; Complex; Cytogenetics; DNA-Directed DNA Polymerase; Data; Development; Diagnostic; Disease; Double Stranded DNA Virus; EBV-associated malignancy; Electron Microscopy; Environmental Risk Factor; Epidemiologic Studies; Epigenetic Process; Epithelial; Epstein-Barr Virus Infections; Etiology; Evaluation; Event; Exhibits; Future; Genes; Genetic; Genetic Heterogeneity; Health; Hematologic Neoplasms; Herpesviridae; Hodgkin Disease; Human; Human Genetics; Human Herpesvirus 4; Inbreeding; Incidence; Individual; Infection; Lymph Node Tissue; Lymphoid; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Malignant lymphoid neoplasm; Modeling; Mutation; Neoplasms; Nucleotides; Oncogenic; Plasma; Play; Predisposition; Process; Publishing; Research; Role; Sampling; Satellite Viruses; Serological; Specimen; Suggestion; Susceptibility Gene; T-Cell Lymphoma; Technology; Testing; Therapeutic; Tissues; Validation; Viral; Viral Genome; Viral Pathogenesis; Virus; Virus Diseases; base; c-myc Genes; clinically relevant; clinically significant; cohort; design; gammaherpesvirus; high risk; innovation; large cell Diffuse non-Hodgkin' s lymphoma; model development; novel; novel therapeutics; particle; pre-clinical; prevent; prospective; tool; tumor initiation; tumor progression; viral DNA; viral detection

DESCRIPTION (provided by applicant): Chronic infection with the prototypic gamma-1 herpesvirus, Epstein-Barr Virus (EBV) in humans is usually asymptomatic, however, infection has been associated with lymphoid and epithelial malignancies in humans. The role of EBV in lymphomagenesis has been difficult to elucidate in part because concurrent genetic and environmental factors that influence viral pathogenesis such as spontaneous chromosomal translocations are difficult to accurately model in the research setting. Spontaneous lymphoma in the domestic dog comprises a large heterogeneous group of malignancies including Diffuse Large B Cell Lymphoma (DLBCL) and Burkitt-like lymphoma, that displaying similar genetic and cytogenetic changes to NHL subtypes in humans. Furthermore, the strong association between dog breed and predisposition to lymphoma indicates that genetic factors play a key role in determining susceptibility to lymphoma. Our preliminary data support and expand recent published findings that domestic dogs harbor an EBV-like gammaherpesvirus and that this may contribute to spontaneous lymphoma in this species. Taken together, these findings suggest that lymphomagenesis in dogs may have a viral etiology and recapitulate the complex interplay of genetic and epigenetic events associated with the viral pathogenesis of lymphoma in humans. In this exploratory proposal, we will explore the central hypothesis that pet dogs are infected with a gammaherpesvirus that has oncogenic potential. We will perform a prospective, longitudinal sero- epidemiological study to evaluate the association between viral infection and the development of B cell lymphoma in the Golden Retriever dog. Golden Retrievers are genetically predisposed to lymphoma and have an exceptionally high incidence of disease (incidence of 1 in 8 dogs). The limited genetic heterogeneity within the breed provides a unique opportunity to identify viral factors and genes that predispose to virus-associated lymphomagenesis in this species and we believe that this will have direct relevance to mechanisms promoting EBV-associated lymphomagenesis in humans. In addition, we aim to take advantage of our unlimited access to canine clinical tissue specimens and serum/plasma samples from dogs with spontaneous B cell lymphoma, to isolate and further characterize the canine EBV-like herpesvirus. We anticipate that our results will form the basis of a future R01 designed to investigate the role of this putative EBV-related herpesvirus in lymphomagenesis in dogs and establish the dog as a clinically relevant, spontaneous model to study viral- associated lymphomagenesis. If our hypothesis is correct, the results from the studies proposed here will have a significant impact on human health, identifying the dog as a clinically relevant, spontaneous, large animal model in which to identify factors influencing viral transformation and to test and advance virus targeted therapies in a pre-clinical setting. PUBLIC HEALTH RELEVANCE: Project narrative Chronic infection with Epstein-Barr Virus (EBV) is usually asymptomatic, however infection has been associated with lymphoid malignancies in humans. In this exploratory proposal we aim to study the association of natural infection with a novel oncogenic canine gammaherpesvirus with the development of lymphoma in the Golden Retriever dog that is genetically predisposed to lymphomagenesis. Development of this model of natural viral infection and spontaneous lymphomagenesis will allow us to evaluate genetic factors that influence viral pathogenesis and provide a clinically relevant large animal model that may be employed in the future to evaluate novel therapies for EBV-associated lymphoproliferative disorders in humans.

描述(申请人提供)：人类慢性感染典型的伽玛-1疱疹病毒，EB病毒(EBV)通常是无症状的，然而，在人类中，感染与淋巴和上皮性恶性肿瘤有关。EBV在淋巴瘤发生中的作用一直很难阐明，部分原因是影响病毒发病的同时存在的遗传和环境因素，如自发的染色体易位，很难在研究环境中准确建模。家犬自发性淋巴瘤包括一大群不同类型的恶性肿瘤，包括弥漫性大B细胞淋巴瘤(DLBCL)和Burkitt样淋巴瘤，其遗传和细胞遗传学变化与人类NHL亚型相似。此外，狗的品种与淋巴瘤易感性之间的强烈关联表明，遗传因素在决定淋巴瘤易感性方面发挥着关键作用。我们的初步数据支持并扩展了最近发表的发现，即家犬携带EBV样伽马疱疹病毒，这可能有助于该物种的自发性淋巴瘤。综上所述，这些发现表明，狗的淋巴肿大可能有病毒病因学，并概括了与人类淋巴瘤的病毒发病相关的遗传和表观遗传事件的复杂相互作用。在这个探索性的提案中，我们将探索中心假设，即宠物狗感染了一种具有致癌潜力的伽玛疱疹病毒。我们将进行一项前瞻性的、纵向的血清流行病学研究，以评估病毒感染与金毛猎犬B细胞淋巴瘤发生之间的关系。金毛寻回犬在遗传上易患淋巴瘤，发病率极高(8只狗中就有1只)。该物种内有限的遗传异质性提供了一个独特的机会来识别该物种中易于发生病毒相关淋巴肿大的病毒因子和基因，我们相信这将与促进人类EBV相关淋巴肿大的机制直接相关。此外，我们的目标是利用我们对犬临床组织样本和自发性B细胞淋巴瘤犬的血清/血浆样本的无限访问优势，分离并进一步鉴定犬EBV样疱疹病毒。我们预计，我们的结果将成为未来R01的基础，旨在调查这种假定的EBV相关疱疹病毒在狗淋巴肿大中的作用，并建立狗作为临床相关的自发模型来研究病毒相关的淋巴肿大。如果我们的假设是正确的，本文提出的研究结果将对人类健康产生重大影响，将狗确定为临床相关的、自发的大型动物模型，在其中确定影响病毒转化的因素，并在临床前环境中测试和推进病毒靶向治疗。 公共卫生相关性：项目叙述爱泼斯坦-巴尔病毒(EBV)慢性感染通常是无症状的，然而感染与人类淋巴系统恶性肿瘤有关。在这个探索性的提案中，我们的目标是研究自然感染一种新的致癌性犬类伽马疱疹病毒与金毛猎犬淋巴瘤的发展之间的关系，因为金毛猎犬在遗传上容易发生淋巴瘤。这种自然病毒感染和自发淋巴肿大模型的发展将使我们能够评估影响病毒发病的遗传因素，并提供一个具有临床意义的大动物模型，该模型可能在未来用于评估人类EBV相关淋巴增生性疾病的新疗法。