Fanconi Anemia as a Model for Susceptibility to Human Papillomavirus Infection

范可尼贫血作为人乳头瘤病毒感染易感性模型

• 批准号: 8087417
• 负责人: Melinda Sue ButschKovacic
• 金额: $ 40.45万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8087417
• 关键词: Adult; Age; B-Lymphocytes; Bone Marrow Transplantation; Brazil; Cell Nucleus; Cells; Child; Child health care; Clinical; Coculture Techniques; Collaborations; Comprehensive Health Care; Cytotoxic T-Lymphocytes; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA copy number; Data; Defect; Development; Diphtheria; Disease; Enrollment; Epidemiology; Family; Fanconi' s Anemia; Funding; Future; General Population; Genes; Genetic; Genomic Instability; Goals; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Health; Heterozygote; Hospitals; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Hypersensitivity; Immune; Immune Targeting; Immunologics; Immunology; Immunophenotyping; In Vitro; Incidence; Individual; Infection; Infection prevention; Inherited; Intervention; Knowledge; Lead; Life; Life Cycle Stages; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Measures; Minnesota; Mission; Mitogens; Modeling; Morbidity - disease rate; Mutation; Natural History; Natural Killer Cells; Oral; Pancytopenia; Parents; Participant; Pathway interactions; Patients; Peptides; Perinatal; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Prevalence; Proteins; Public Health; Publishing; Race; Radiation; Recommendation; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Route; Siblings; Source; Specimen; Squamous Cell; Squamous cell carcinoma; Testing; Tetanus; Time; United States National Institutes of Health; Universities; Vaccination; Vulnerable Populations; Work; base; burden of illness; cancer prevention; cancer therapy; chemotherapy; cytokine; extracellular; high risk; immune function; improved; innovation; insight; keratinocyte; mortality; multidisciplinary; novel; outcome forecast; peripheral blood; prevent; response; transmission process; treatment strategy; tumor; tumor growth; viral DNA

DESCRIPTION (provided by applicant): The overall objective of this R01 application is to characterize the epidemiology of and host immunological responses to human papillomavirus (HPV) infection in individuals with Fanconi anemia (FA) and their families. Currently, there remains an incomplete understanding of the extent to which abnormal FA-related DNA repair and immune dysregulation contribute to early HPV acquisition, maintenance and/or susceptibility to cancer. As FA results from mutations in one of 14 genes whose respective protein products assemble in the nucleus to repair DNA damage, those afflicted have considerable genome instability, progressive bone marrow failure and predisposition to head and neck and gynecological squamous cell carcinomas (SCC). FA therefore is an excellent model in which to understand the mechanisms underlying the risk of typically HPV-related cancers particularly in vulnerable populations. While there are known associations between HPV infection and SCC in the general population, the degree to which these SCCs are associated with HPV infection in individuals with FA is unclear. Our preliminary data indicate that activation of the FA-related DNA repair pathway limits the HPV life cycle under normal circumstances and prevents malignant transformation. Further, the observed increased oral HPV prevalence in individuals with FA compared to controls indicates that keratinocytes deficient in FA-related genes uniquely support HPV infection and/or replication. Importantly, abnormal immunologic studies point to the presence of specific immune deficiencies in children with FA that may also contribute to the observed propensity to HPV. To test our central hypothesis that individuals with FA are uniquely susceptible to HPV infection, we will pursue the following two Specific Aims: 1) determine the prevalence, incidence and type-specific persistence of infection with 37 HPV subtypes in individuals with FA and their parents (obligate heterozygotes) and siblings (potential heterozygotes; possible sources of HPV); and 2) characterize the immunological basis (primarily natural killer cell, cytotoxic T-lymphocyte, and B cell phenotype/function) for HPV infection in individuals with FA. The study capitalizes on the strong collaboration of distinctive FA clinical groups in Cincinnati, Minnesota and Brazil, established relationships with the Fanconi Anemia Research Fund, and proven expertise in HPV typing, immunophenotyping and epidemiological analyses. This innovative research will undoubtedly provide insight into the possible mechanisms underlying the observed risks of SCC in vulnerable individuals such as those with FA as well as how genes modulating the FA-related DNA repair pathway may represent genetic modifiers of HPV infection in the general population. These significant contributions are expected to lead to development of improved cancer prevention and treatment strategies for individuals more susceptible to infection-induced cancers. Importantly, our study will positively impact child health now by providing evidence for recommendations for HPV vaccination in individuals with FA. PUBLIC HEALTH RELEVANCE: The proposed R01 application is significant to public health because it will point to possible mechanisms underlying the observed increased risk of typically human papillomavirus (HPV)-associated squamous cell cancers in genetically vulnerable populations such as those with Fanconi anemia (FA) as well as help researchers understand the role(s) of proteins in the FA-related DNA repair pathway in modifying HPV infection in the general population. Consequently, the proposed research is relevant to the NIH mission of developing fundamental knowledge that will enhance health, lengthen life, and reduce the burden of illnesses such as those at high risk for squamous cell malignancies.

描述（由申请人提供）：本 R01 申请的总体目标是表征范可尼贫血 (FA) 及其家人的人乳头瘤病毒 (HPV) 感染的流行病学和宿主免疫反应。目前，对于 FA 相关 DNA 修复异常和免疫失调在多大程度上导致早期 HPV 获得、维持和/或癌症易感性的程度尚不完全了解。由于 FA 是由 14 个基因之一的突变引起的，这些基因各自的蛋白质产物在细胞核中组装以修复 DNA 损伤，因此患者具有相当大的基因组不稳定、进行性骨髓衰竭以及头颈癌和妇科鳞状细胞癌 (SCC) 的易感性。因此，FA 是一个很好的模型，可以用来了解典型 HPV 相关癌症的风险机制，特别是在弱势群体中。尽管已知一般人群中 HPV 感染与鳞状细胞癌之间存在关联，但这些鳞状细胞癌与 FA 个体中的 HPV 感染的相关程度尚不清楚。我们的初步数据表明，FA相关DNA修复途径的激活限制了正常情况下的HPV生命周期并防止恶性转化。此外，与对照组相比，观察到 FA 个体口腔 HPV 患病率增加表明，缺乏 FA 相关基因的角质形成细胞独特地支持 HPV 感染和/或复制。重要的是，异常的免疫学研究表明 FA 儿童存在特异性免疫缺陷，这也可能导致观察到的 HPV 倾向。为了检验我们的中心假设，即 FA 个体特别容易感染 HPV，我们将追求以下两个具体目标：1) 确定 FA 个体及其父母中 37 种 HPV 亚型感染的患病率、发病率和类型特异性持续性（专性杂合子）和兄弟姐妹（潜在杂合子；HPV 的可能来源）； 2) 描述 FA 个体 HPV 感染的免疫学基础（主要是自然杀伤细胞、细胞毒性 T 淋巴细胞和 B 细胞表型/功能）。该研究利用了辛辛那提、明尼苏达州和巴西独特 FA 临床小组的强有力合作，与 Fanconi 贫血研究基金建立了关系，以及在 HPV 分型、免疫表型和流行病学分析方面经过验证的专业知识。这项创新研究无疑将深入了解脆弱个体（例如 FA 患者）中观察到的 SCC 风险的可能机制，以及调节 FA 相关 DNA 修复途径的基因如何代表一般人群中 HPV 感染的遗传修饰因子。这些重大贡献预计将导致针对更容易感染感染诱发癌症的个体开发改进的癌症预防和治疗策略。重要的是，我们的研究将为 FA 患者提供 HPV 疫苗接种建议的证据，从而对儿童健康产生积极影响。 公共卫生相关性：拟议的 R01 申请对公共卫生具有重要意义，因为它将指出在遗传易感人群（例如范可尼贫血 (FA) 患者）中观察到的典型人乳头瘤病毒 (HPV) 相关鳞状细胞癌风险增加的可能机制。以及帮助研究人员了解 FA 相关 DNA 修复途径中蛋白质在改变普通人群 HPV 感染方面的作用。因此，拟议的研究与 NIH 的使命相关，即发展基础知识，以增强健康、延长寿命并减轻疾病负担，例如鳞状细胞恶性肿瘤高风险疾病的负担。