Hamster Model of SV40 Infection and Disease

SV40 感染和疾病的仓鼠模型

• 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
• 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

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）：人类癌症病毒在宿主中建立持续感染。我们假设病毒诱发癌症的风险取决于病毒宿主相互作用的早期事件，从而导致建立持续性病毒感染的病毒载量升高。现在已经认识到多瘤病毒SV40可以引起人类感染，并且可以在选定的人类癌症中检测到。尚未探索导致癌症发展的体内SV40感染期间的早期事件。该项目将利用仓鼠模型来识别和表征与SV40感染和随后的癌变有关的病毒遗传因素和宿主反应。具体目标1将识别仓鼠中影响SV40急性和慢性感染模式的病毒遗传因素。野生型SV40和匹配的SV40应变特异性区域不同的构建体将检查调节区域，T-抗原可变结构域以及SV40 microRNA对体内急性和慢性感染对急性和慢性感染的影响。具体目标2将定义病毒遗传因素对SV40介导的恶性疾病的发展的贡献。通过不同的给药途径暴露于SV40遗传变异的仓鼠中的肿瘤发生率将与急性和慢性SV40感染的建立和病毒载量有关。使用非侵入性超声检查和分析肿瘤进展过程中病毒表达的变化将检测到早期淋巴瘤。特定的目标3将确定SV40对淋巴样细胞和宿主对感染的反应的影响。 SV40与培养的仓鼠淋巴样细胞的相互作用将根据病毒表达和细胞永生化定义。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。 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感染的生物学以及与SV40参与人类恶性肿瘤有关的机制产生重大的新理解。对病毒发病机理早期事件的新见解将适用于人类的多瘤病毒感染，并可能识别出多瘤病毒疗法发展的新靶标。公共卫生相关性：多瘤病毒引起癌症，肾脏疾病和神经系统疾病。该建议将确定病毒遗传因素和宿主反应的相互作用，从而导致慢性病毒感染和随后的疾病发展。该项目将对与多瘤病毒和人类癌有关的机制提供新的理解，并可能确定治疗多瘤病毒感染和预防疾病的新型靶标。