University of New Mexico Interdisciplinary HPV Prevention Center

新墨西哥大学跨学科 HPV 预防中心

• 批准号: 7736498
• 负责人: Cosette Marie Wheeler
• 金额: $ 258.59万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 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/7736498
• 关键词: University; New; Mexico; Interdisciplinary; HPV

DESCRIPTION (provided by applicant): Over 6 million new cases of sexually transmitted human papillomavirus (HPVs) infections are reported every year making HPV the most common sexually transmitted agent world-wide. At least 15 carcinogenic HPV types cause virtually all cervical cancers however; the costly HPV vaccine licensed in 2006 covers only HPV types 6/11/16/18 and has no therapeutic effect on established infections. Thus all women must continue routine cervical screening at a US cost of $4-5 billion annually. More importantly, the majority of women alive today are still at risk for developing cervical cancer. In addition, the current vaccine program presently leaves all men unprotected. Given these considerations and the fact that cervical cancer is a disease of disparities, it is unlikely that projected disease reductions will be realized with current strategies. Programs to characterize current US HPV vaccine implementation and effectiveness are needed and continuing efforts to better understand HPV biology and to develop broadly protective prevention strategies and therapeutics for existing infections remain critical. The specific aims of this application are: 1) To establish the University of New Mexico Interdisciplinary HPV Prevention Center that incorporates research approaches to address these gaps in knowledge. 2) To fund and support 4 projects representing a spectrum of interdisciplinary approaches including: A) modeling of PV-host interactions in 3 dimensions to define elements of epithelial cell biology and immunity that contribute to the pathogenesis and prevention of infections; B) utilizing novel vaccine strategies based on virus-display technology to generate broad protection against a majority of HPV infections; C) utilizing a unique bioinformatics system that captures all events of a US population-based cervical screening program to characterize implementation and effectiveness of primary and secondary HPV interventions; and D) developing a set of web-based tools to promote the informed adoption of HPV and other STI prevention. 3) To establish 2 cores housing shared resources to support these interdisciplinary research approaches: A) a biostatistics and bioinformatics core and B) a virus infection core supporting technologies for virus production, quantitation, and animal imaging and housing a biospecimen resource. PROJECT 1: GENITAL PAPILLOMAVIRUS INFECTIONS IN EPITHELIAL TISSUES (OZBUN, M.) PROJECT 1 DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：每年报告的性传播人乳头瘤病毒（HPV）感染的新病例超过600万例，使HPV成为世界范围内最常见的性传播媒介。然而，至少有15种致癌的HPV类型导致几乎所有的宫颈癌; 2006年批准的昂贵的HPV疫苗仅涵盖HPV 6/11/16/18型，对已建立的感染没有治疗效果。因此，所有妇女都必须继续进行常规宫颈筛查，美国每年的费用为40亿至50亿美元。更重要的是，今天活着的大多数妇女仍然有患宫颈癌的风险。此外，目前的疫苗计划使所有男子都得不到保护。考虑到这些因素以及宫颈癌是一种差异性疾病的事实，目前的战略不太可能实现预计的疾病减少。目前美国HPV疫苗的实施和有效性的特点的计划是必要的，继续努力，以更好地了解HPV生物学和开发广泛的保护性预防策略和治疗现有的感染仍然至关重要。本申请的具体目的是：1）建立新墨西哥州大学跨学科HPV预防中心，该中心采用研究方法来解决这些知识差距。2)资助和支持代表一系列跨学科方法的4个项目，包括：A）在3个维度上建模PV与宿主相互作用，以定义有助于感染发病机制和预防的上皮细胞生物学和免疫学要素; B）利用基于病毒展示技术的新型疫苗策略，对大多数HPV感染产生广泛保护; C）利用独特的生物信息学系统，捕获美国基于人群的宫颈筛查计划的所有事件，以表征初级和二级HPV干预措施的实施和有效性;以及D）开发一套基于网络的工具，以促进HPV和其他STI预防的知情采用。3)建立2个核心，容纳共享资源，以支持这些跨学科研究方法：A）生物统计学和生物信息学核心和B）病毒感染核心，支持病毒生产、定量和动物成像技术，并容纳生物标本资源。 项目1：上皮组织中的生殖器乳头瘤病毒感染（OzBUN，M.） 项目1描述（由申请人提供）：超过100种类型的人乳头瘤病毒（HPV）感染粘膜和皮肤上皮，引起良性和恶性肿瘤。每年报告约620万例HPV性传播感染（STI）新病例;美国目前有超过2000万人感染，HPV被认为是全球最常见的已知STI。总的来说，数据表明，单一的性行为可以促进感染，这表明病毒是相当有效的体内传播媒介。最近，我们已经能够在实验室中生产高滴度HPV原液。我们在细胞培养研究中使用感染性HPV病毒粒子的研究以及我们的同事对动物PV的研究表明，这些病毒通常在体外引起感染的能力很差。因此，我们假设目前的单层细胞培养PV感染模型系统不能准确地再现体内感染过程。事实上，生殖器HPV相关感染研究的主要缺陷包括缺乏高滴度的感染性病毒库，以及缺乏适当的基于组织的模型系统来研究早期感染、发病机制和干预措施。我们的中心假设是单层细胞培养不能显示上皮组织HPV感染的基本方面，并且HPV感染建立的重要特征可以从三维（3-D）组织模型中确定。我们将使用高滴度的HPV病毒体储备来实现该计划的目标，即建立更具生理相关性的HPV生殖器感染的三维组织模型，并回答有关启动生产性HPV感染的基本和重要问题。为了解决我们的中心假设，我们将追求具体的目标，包括三个生物集成，越来越复杂的系统方面的性传播PV感染。在目标1中，我们将定义体外分化上皮细胞中HPV感染的要求。在目标2中，我们将使用啮齿动物生殖器感染模型来鉴定易受HPV感染的细胞类型，并进一步确定创伤如何增强体内感染。在目标3中，我们将在我们的STI HPV感染的非人模型的背景下评估生殖器PV感染的建立，其中可以评估灵长类动物解剖学和免疫应答。生殖器PV结合和感染的具体方面的假设提出，无论是支持或反驳，我们将增加我们的HPV靶细胞相互作用的分子机制和上皮组织感染的生物学，大大欠研究领域的理解。我们预计这项工作将直接影响未来广泛的交叉保护性预防和治疗策略的发展，以预防持续性HPV STI。