Hamster Model of SV40 Infection and Disease

SV40 感染和疾病的仓鼠模型

基本信息

批准号：
8193224
负责人：
JANET S BUTEL
金额：
$ 30.9万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2009-07-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8193224
关键词：
Acute Affect Antibody Formation Biological Assay Biology Cancer Etiology Chronic Data Development Disease Disease Outcome Event Gene Expression Goals Hamsters Health Human Immune response Incidence Infection Interleukin-10 Kidney Diseases Laboratories Lead Lymphocyte Lymphoid Cell Lymphoma Malignant - descriptor Malignant Neoplasms Measures Mediating MicroRNAs Modeling Neurologic Nucleic Acid Regulatory Sequences Outcome Pathogenesis Pattern Play Polyomavirus Polyomavirus Infections Reagent Research Risk Role Route Simian virus 40 Staging Therapeutic Tissues Ultrasonography Viral Viral Genes Viral Load result Viral Pathogenesis Viral Tumor Antigens Virus Virus Diseases Work carcinogenesis cell immortalization cell type cytokine defined contribution design genetic variant in vivo innovation insight new therapeutic target novel prevent programs success tumor tumor progression viral DNA virus genetics virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Human cancer viruses establish persistent infections in their hosts. We hypothesize that the risk of viral induced cancer is dependent on early events in virus-host interactions that lead to the establishment of persistent viral infections with elevated viral loads. It is now recognized that polyomavirus SV40 can cause human infections and can be detected in selected human cancers. Early events during SV40 infections in vivo that lead to cancer development have not been explored. This project will utilize the hamster model to identify and characterize virus genetic factors and host responses involved in the pathogenesis of SV40 infections and subsequent carcinogenesis. Specific Aim 1 will identify viral genetic factors that influence patterns of SV40 acute and chronic infections in hamsters. Wild-type SV40 and matched constructs that differ in SV40 strain-specific regions will examine the influence of the regulatory region, the T-antigen variable domain, and SV40 microRNA on establishment of acute and chronic infections in vivo and on viral loads. Specific Aim 2 will define the contribution of viral genetic factors to the development of SV40-mediated malignant disease. Tumor incidences in hamsters exposed to SV40 genetic variants by different routes of administration will be related to the establishment and viral loads of acute and chronic SV40 infections. Early-stage lymphomas will be detected using noninvasive ultrasound and changes in viral expression during tumor progression analyzed. Specific Aim 3 will determine SV40 effects on lymphoid cells and on host responses to infection. The interactions of SV40 with cultured hamster lymphoid cells will be defined with respect to viral expression and cell immortalization. Host responses involving cytokine expression and antibody production will be evaluated in the context of establishment and outcome of virus infections. The potential roles of SV40 microRNA and of cytokine IL-10 in modulating host responses to SV40 infections will be explored. The innovative design of this project will yield significant new understandings of the biology of SV40 infections and of mechanisms relevant to SV40 involvement in human malignancies. New insights into early events in viral pathogenesis will be applicable to polyomavirus infections in humans and may identify novel targets for the development of polyomavirus therapeutics. PUBLIC HEALTH RELEVANCE: Polyomaviruses cause cancer, kidney disease, and neurologic disease. This proposal will identify the interactions of virus genetic factors and host responses that lead to chronic viral infections and subsequent disease development. This project will provide new understandings of mechanisms relevant to polyomaviruses and human cancer and may identify novel targets for therapeutics to treat polyomavirus infections and prevent disease.

描述（由申请人提供）：人类癌症病毒在其宿主体内建立持续感染。我们假设病毒诱发癌症的风险取决于病毒与宿主相互作用的早期事件，这些事件导致病毒载量升高的持续病毒感染的建立。现在人们认识到多瘤病毒 SV40 可以引起人类感染，并且可以在某些人类癌症中检测到。体内 SV40 感染期间导致癌症发展的早期事件尚未被探索。该项目将利用仓鼠模型来识别和表征与 SV40 感染发病机制和随后的致癌作用有关的病毒遗传因素和宿主反应。具体目标 1 将确定影响仓鼠 SV40 急性和慢性感染模式的病毒遗传因素。野生型 SV40 和 SV40 菌株特异性区域不同的匹配构建体将检查调节区、T 抗原可变结构域和 SV40 microRNA 对体内急性和慢性感染的建立以及病毒载量的影响。具体目标 2 将定义病毒遗传因素对 SV40 介导的恶性疾病发展的贡献。通过不同给药途径暴露于 SV40 基因变异的仓鼠的肿瘤发病率将与急性和慢性 SV40 感染的建立和病毒载量有关。将使用无创超声检测早期淋巴瘤，并分析肿瘤进展过程中病毒表达的变化。具体目标 3 将确定 SV40 对淋巴细胞和宿主对感染的反应的影响。 SV40 与培养的仓鼠淋巴细胞的相互作用将在病毒表达和细胞永生化方面进行定义。涉及细胞因子表达和抗体产生的宿主反应将在病毒感染的建立和结果的背景下进行评估。将探讨 SV40 microRNA 和细胞因子 IL-10 在调节宿主对 SV40 感染的反应中的潜在作用。该项目的创新设计将对 SV40 感染的生物学以及 SV40 参与人类恶性肿瘤的相关机制产生重要的新认识。对病毒发病机制早期事件的新见解将适用于人类多瘤病毒感染，并可能确定多瘤病毒疗法开发的新靶标。公共卫生相关性：多瘤病毒会导致癌症、肾脏疾病和神经系统疾病。该提案将确定导致慢性病毒感染和随后疾病发展的病毒遗传因素和宿主反应之间的相互作用。该项目将提供对多瘤病毒和人类癌症相关机制的新认识，并可能确定治疗多瘤病毒感染和预防疾病的新靶点。