Characterization of an animal model of chronic infection and disease

慢性感染和疾病动物模型的表征

基本信息

批准号：
7642162
负责人：
Linda F. Van Dyk
金额：
$ 7.7万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-08 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7642162
关键词：
Animal Model B-Cell Lymphomas B-Lymphocytes Benign Biological Models Cells Chronic Chronic Disease Clonality Critical Pathways Defect Development Disease Disease Outcome Disease model Employee Strikes Environmental Risk Factor Future Gene Expression Genetic Goals HIV Human Human Herpesvirus 4 Immune Immunologic Deficiency Syndromes Individual Infection Inflammation Inflammatory Interferon Type II Kaposi Sarcoma Lead Lesion Lung Lung Lymphoma Lymphoma Lymphomagenesis Lymphoproliferative Disorders Malignant Neoplasms Modeling Molecular Mus Nature Neoplasms Outcome Pilot Projects Pneumonia Satellite Viruses Staging Testing Time Ursidae Family Viral Viral Genes Virus Virus Diseases base cell type cohort cytokine gammaherpesvirus infected B cell insight mouse model neoplastic cell public health relevance translational study tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Gammaherpesviruses cause lifelong infection and are associated with various diseases, particularly in immune deficient hosts. The human gammaherpesviruses, Epstein Barr virus (EBV) and Kaposi's sarcoma associated virus, are associated with a number of malignancies, including lymphoproliferative disease and lymphomas. Murine gammaherpesvirus-68 is a genetically and biologically conserved with the human gammaherpesviruses, and naturally infects mice. We recently identified that gammaherpesvirus-68 infection of mice unresponsive to the cytokine interferon-gamma results in significant angiocentric inflammation in the lung with variable progression to frank lymphoma within five to nine months of infection. The inflammatory lesions in these individuals are rich in B cells and in virus-infected cells, and the resulting lymphomas are composed primarily of virus-infected B cells. These lesions and lymphomas bear striking similarity to human pulmonary lymphomas associated with chronic virus infection (including EBV). In this proposal for a pilot study, our goal is to extend our initial characterization of these immunodeficiency-associated lymphomas. First, we propose to finalize basic characterization of full cohorts of interferon-gamma unresponsive mice that are mock treated or infected with gammaherpesvirus for up to one year. We will determine tumor-free survival, tumor cell type and virus infection status of lymphoma cells. Second, we will characterize clonality, cell type composition, and virus gene expression of these immunodeficiency- associated lymphomas. Our long-term goal for these studies is the development of a small animal model for immunodeficiency-associated lymphomagenesis that will elucidate the molecular mechanisms that contribute to chronic infection-associated malignancies, to gain new insights into similar human neoplasms and facilitate translational studies. PUBLIC HEALTH RELEVANCE: Characterization of an animal model of chronic infection and disease. Chronic virus infection and immune defects can lead to variable disease outcomes. This pilot study will provide a valuable model system to further our understanding of human pulmonary lymphomas. This study of inflammation and lymphoma associated with chronic virus infection will set the stage for future studies to define the genetic and environmental risks for these tumors, the viral and host contributors to tumor progression, and the critical pathways that could be disrupted for successful therapies.

描述（由申请人提供）：伽马广播病毒会引起终生感染，并与各种疾病有关，尤其是在免疫缺陷宿主中。人γ掌病毒，爱泼斯坦Barr病毒（EBV）和Kaposi的肉瘤相关病毒与许多恶性肿瘤有关，包括淋巴增生性疾病和淋巴瘤。鼠γγ病毒-68是一种遗传和生物学保守的人，用人γ掌病毒保守，自然感染小鼠。我们最近确定，小鼠对细胞因子干扰素 - 伽马无反应的伽马病病毒-68感染导致肺部显着的血管中心炎症，在感染的五到九个月内向坦率的淋巴瘤发展可变。这些个体中的炎症病变富含B细胞和病毒感染的细胞，所得淋巴瘤主要由病毒感染的B细胞组成。这些病变和淋巴瘤与与慢性病毒感染相关的人类肺淋巴瘤（包括EBV）具有惊人的相似性。在这项试点研究的建议中，我们的目标是扩展我们对这些免疫缺陷相关淋巴瘤的初始表征。首先，我们建议最终确定对干扰素无响应的小鼠的基本表征，这些小鼠被模拟治疗或感染了γ鞘膜病毒，长达一年。我们将确定淋巴瘤细胞的无肿瘤存活，肿瘤细胞类型和病毒感染状态。其次，我们将表征这些免疫缺陷型淋巴瘤的克隆性，细胞类型组成和病毒基因表达。这些研究的长期目标是开发一种用于免疫缺陷相关的淋巴作用的小动物模型，该模型将阐明有助于慢性感染相关的恶性肿瘤的分子机制，从而获得对类似人类的人类肿瘤的新见解，并促进转化。公共卫生相关性：慢性感染和疾病动物模型的表征。慢性病毒感染和免疫缺陷会导致可变的疾病预后。这项试验研究将提供一个有价值的模型系统，以进一步了解我们对人类肺淋巴瘤的理解。这项与慢性病毒感染相关的炎症和淋巴瘤的研究将为未来的研究奠定阶段，以定义这些肿瘤的遗传和环境风险，肿瘤进展的病毒和宿主贡献者，以及可能破坏成功疗法的关键途径。