Genital Papillomavirus Infections in Epithelial Tissues

上皮组织中的生殖器乳头瘤病毒感染

基本信息

批准号：
7763574
负责人：
Michelle A Ozbun
金额：
$ 30.55万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
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：
2009-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7763574
关键词：
3-Dimensional Address Affect Anatomy Animals Area Benign Binding Biological Models Biology Cell Communication Cell Culture Techniques Cells Clinical Complex Cutaneous DNA biosynthesis Data Developed Countries Developing Countries Development Disease Epithelial Epithelium Exocervix Extracellular Matrix Filopodia Future Gene Expression Genes Genetic Transcription Genital system Goals Human Human Papillomavirus Immune response In Vitro Incidence Infection Intervention Laboratories Malignant - descriptor Malignant Neoplasms Mitotic Modeling Molecular Morbidity - disease rate New Mexico Outcome Papillomavirus Infections Pathogenesis Peripheral Blood Mononuclear Cell Physiology Prevention Primates Process Publishing Reporting Risk Rodent Sexually Transmitted Agents Sexually Transmitted Diseases Stratified Epithelium Stratum Basale System Testing Therapeutic Time Tissue Model Tissues Universities Vaccines Vagina Viral Viral Genes Viral Genome Viral Pathogenesis Virion Virus Woman Work base cell type chemokine cytokine design genital infection improved in vivo innovation men monolayer neutralizing antibody prevent programs prophylactic response uptake viral DNA viral RNA virus host interaction

项目摘要

Over 100 types of human papillomaviruses (HPVs) infect mucosal and cutaneous epithelium, causing benign and malignant tumors. About 6.2 million new cases of HPV sexually transmitted infections (STIs) are reported every year; >20 million people in the US are currently infected, and HPV is considered as the most common known STI worldwide. Overall, data suggest that a single sexual act can promote infection, indicating that the viruses are quite effective transmissible agents in vivo. Recently, we have been able to produce high-titer HPV stocks in the laboratory. Our studies using infectious HPV virions in cell culture studies and our colleagues' work with animal PVs indicate the viruses in general are poor at causing infections in vitro. We therefore postulate that the current monolayer cell culture PV infection model systems fail to accurately recapitulate the infectious process in vivo. Indeed, the major deficiencies in the study of genital HPV-related infections have included the lack of high titer infectious viral stocks and the lack of appropriate tissue-based model systems with which to study early infections, pathogenesis, and interventions. Our CENTRAL HYPOTHESIS is that monolayer cell cultures fail to display essential aspects of epithelial tissue HPV infections and important features of HPV infection establishment can be determined from 3-dimensional (3-D) tissue-based models. We will use high titer HPV virion stocks to pursue this program's goals, which are to establish more physiologically relevant 3-D tissue models of HPV genital infections and to answer basic and essential questions about the initiation of productive HPV infections. To address our central hypothesis, we will pursue SPECIFIC AIMS that encompass three biologically integrated, and increasingly complex systems with regard to sexually transmitted PV infections. In Aim 1 we will define requirements for HPV infection of cells in differentiated epithelium in vitro. In Aim 2 we will use a rodent genital infection model to identify the cell types that are susceptible to HPV infection and to further determine how wounding potentiates infection in vivo. In Aim 3 we will evaluate genital PV infection establishment in the context of our non-human model of STI HPV infections wherein primate anatomy and immune response can be assessed. Hypotheses regarding specific aspects of genital PV binding and infection are posed so that whether supported or refuted, we will increase our understanding of the molecular mechanisms of HPV-target cell interactions and the biology of epithelial tissue infection, areas vastly understudied. We expect this work will directly impact future development of broadly cross-protective prophylactic and therapeutic strategies for preventing persistent HPV STIs

超过 100 种人乳头瘤病毒 (HPV) 感染粘膜和皮肤上皮，导致良性病变和恶性肿瘤。约 620 万新发 HPV 性传播感染 (STI) 病例每年都有报告；目前美国有超过 2000 万人被感染，HPV 被认为是最常见的感染者。世界范围内常见的性病。总体而言，数据表明单次性行为可以促进感染，表明病毒在体内是非常有效的传播媒介。最近，我们能够在实验室生产高滴度 HPV 库存。我们在细胞培养中使用传染性 HPV 病毒粒子的研究研究和我们同事对动物 PV 的研究表明，一般来说，病毒很难引起体外感染。因此，我们假设当前的单层细胞培养 PV 感染模型系统无法准确地再现体内感染过程。事实上，研究的主要缺陷生殖器 HPV 相关感染包括缺乏高滴度传染性病毒库存和缺乏适当的基于组织的模型系统，用于研究早期感染、发病机制和干预措施。我们的中心假设是单层细胞培养物无法表现出必需的上皮组织HPV感染的各个方面以及HPV感染建立的重要特征可以通过基于 3 维 (3-D) 组织的模型来确定。我们将使用高滴度 HPV 病毒粒子股票以实现该计划的目标，即建立更多生理相关的 3D 组织模型 HPV 生殖器感染，并回答有关生产性 HPV 启动的基本和重要问题感染。为了解决我们的中心假设，我们将追求包含三个的具体目标关于性传播真性红斑狼疮感染的生物整合且日益复杂的系统。在目标 1 中，我们将定义体外分化上皮细胞 HPV 感染的要求。目标 2 我们将使用啮齿动物生殖器感染模型来识别易受 HPV 感染的细胞类型，并进一步确定受伤如何增强体内感染。在目标 3 中，我们将评估生殖器 PV 在我们的非人类 STI HPV 感染模型中建立感染，其中灵长类动物可以评估解剖学和免疫反应。关于生殖器 PV 特定方面的假设结合和感染的提出，无论是支持还是反驳，我们都会增加我们对 HPV-靶细胞相互作用的分子机制和上皮组织感染的生物学，领域未被充分研究。我们预计这项工作将直接影响广泛交叉保护的未来发展预防持续性 HPV STI 的预防和治疗策略