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: 8691999
• 负责人: Melinda Sue ButschKovacic
• 金额: $ 37.46万
• 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/8691999
• 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 Papilloma Virus Vaccination; 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.

描述(由申请人提供)：本R01申请的总体目标是描述范科尼贫血(FA)患者及其家庭中人乳头瘤病毒(HPV)感染的流行病学和宿主免疫反应。目前，对于FA相关的DNA修复异常和免疫失调在多大程度上促进了HPV的早期感染、维持和/或对癌症的易感性，人们仍未完全了解。由于FA是由14个基因中的一个突变引起的，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，这些患者具有相当大的基因组不稳定、进行性骨髓衰竭和头颈部和妇科鳞状细胞癌(SCC)的易感性。因此，FA是一个很好的模型，可以用来了解典型的HPV相关癌症风险的潜在机制，特别是在脆弱人群中。虽然在普通人群中HPV感染与鳞状细胞癌之间存在已知的关联，但在FA患者中，这些SCC与HPV感染的关联程度尚不清楚。我们的初步数据表明，在正常情况下，FA相关的DNA修复途径的激活限制了HPV的生命周期，并防止了恶性转化。此外，在FA患者中观察到的口腔HPV感染率与对照组相比增加，这表明缺乏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，异常的免疫学研究指出，FA儿童中存在特定的免疫缺陷，这也可能导致观察到的HPV倾向。为了验证我们的核心假设，即FA患者唯一容易感染HPV的人，我们将追求以下两个具体目标：1)确定FA患者及其父母(专有杂合子)和兄弟姐妹(潜在杂合子；可能的HPV来源)中37种HPV亚型的感染率、发病率和特定类型的持久性；以及2)表征FA患者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)。这项研究利用了辛辛那提、明尼苏达和巴西独特的FA临床小组的强大合作，与范科尼贫血研究基金建立了关系，并在HPV分型、免疫表型和流行病学分析方面拥有成熟的专业知识。这项创新的研究无疑将深入了解在FA等脆弱个体中观察到的鳞状细胞癌风险的可能机制，以及调控FA相关DNA修复途径的基因如何代表普通人群中HPV感染的遗传修饰物。这些重大贡献预计将导致为更容易感染诱发癌症的个人制定更好的癌症预防和治疗策略。重要的是，我们的研究将为FA患者接种HPV疫苗的建议提供证据，从而对儿童健康产生积极影响。