Mechanistic Investigations of Ethnic Differences in HPV Variants

HPV 变异种族差异的机制研究

基本信息

批准号：
8708011
负责人：
Craig M Meyers
金额：
$ 30.06万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708011
关键词：
Acute African Asian Americans Asians Basic Cancer Research Biological Biological Assay Biology Capsid Proteins Cell Line Cells Cervix Neoplasms Clinical Clinical Data Epidemiology Epithelial Ethnic Origin Ethnic group European Exhibits Family Founder Effect Genes Genetic Genetic Determinism Genome Geographic Distribution Geography German population Goals Human Papillomavirus Human papillomavirus 16 In Vitro Incidence Individual Infection Investigation Knowledge Life Cycle Stages Measures Minority Mission Nucleic Acid Regulatory Sequences Population Population Study Positioning Attribute Predisposition Prevalence Production Proteins Public Health Race Research Resources Tissues Variant Viral Virus cancer health disparity carcinogenicity ethnic difference genome analysis keratinocyte mRNA Differential Displays prototype public health relevance tissue/cell culture tool

项目摘要

DESCRIPTION (provided by applicant): Genotypic variants of HPV16 are defined as having less than 2% differences in the major capsid protein gene with respect to the prototype genome have been identified worldwide. A body of epidemiological and clinical data has emerged associating groups of HPV16 variants with differences in the clinical progression and aggressiveness of the cervical neoplasia. Representative variants from all major HPV16 variant lineages are detected in populations worldwide, although specific prevalences differ by geography. Infection and oncogenicity of specific HPV variants appears to vary geographically and also with the ethnic origin of the population studied. The greatest predictor of variant lineage is race. Variants, especially those associated with ethnic populations of African or Asian descent have a greater predisposition for persistence. Attempts have been made to correlate the differences in the clinical picture exhibited by HPV16 variants with the biology and life cycle of the virus. However, the majority of these studies have analyzed functions of specific genes or regions of the virus in isolation, such as the E6 gene product or the upper regulatory region. To unequivocally evaluate causal genetic effects, whole-genomes analyses are needed. There have been no whole-genome studies relating to the viral life cycle and infectivity, and how this may be related to the ethnicity. Our ability to reproduce in vitro the complete viral life cycle, including production of infectious virus, places us in a position to propose whole-genome analyses of the HPV16 variants. We also have the tools and expertise to investigate interaction of HPV16 variants with ethnic-specific host tissues. Our long-term goal is to understand ethnic differences in HPV variants using a whole-genome analyses, including infection prevalence and carcinogenicity. As far as we can tell this will be the first whole-genome analyses of any HPV variant. The specific objectives of this proposal are to compare European HPV16 variants with the two African HPV16 variant groups (African-1 and African-2) and the Asian American variant group. The central hypothesis is that ethnic associated variants differ mechanistically in infectivity and carcinogenicity and that these differences are especially acute in epithelial tissus of individuals of the ethnic backgrounds associated with the variant. We will pursue these studies in three specific aims: Specific Aim 1: Investigate differences in the carcinogenic proclivity of ethnic-specific HPV16 variants. Specific Aim 2: Compare infectivity of HPV16 variants ethnic-specific keratinocytes. Specific Aim 3: Identify genetic determinants responsible for ethnic-specific biological differences of HPV16 variants.

描述（由申请人提供）：HPV16 的基因型变体被定义为主要衣壳蛋白基因相对于世界范围内已鉴定的原型基因组的差异小于 2%。大量流行病学和临床数据将 HPV16 变种组与宫颈肿瘤的临床进展和侵袭性差异联系起来。尽管具体患病率因地理位置而异，但所有主要 HPV16 变体谱系的代表性变体均在全世界人群中检测到。特定 HPV 变体的感染和致癌性似乎因地域以及所研究人群的种族起源而异。变异谱系的最大预测因素是种族。变体，尤其是那些与非洲或亚洲血统的种族相关的变体，更容易持续存在。已尝试将 HPV16 变种所表现出的临床表现差异与生物学和生命周期联系起来病毒的。然而，这些研究大多数都是孤立分析病毒特定基因或区域的功能，例如E6基因产物或上调控区。为了明确评估因果遗传效应，需要进行全基因组分析。目前还没有与病毒生命周期和传染性以及这与种族有何关系相关的全基因组研究。我们能够在体外复制完整的病毒生命周期，包括感染性病毒的产生，这使我们能够对 HPV16 变体进行全基因组分析。我们还拥有研究 HPV16 变体与种族特异性宿主组织相互作用的工具和专业知识。我们的长期目标是通过全基因组分析了解 HPV 变异的种族差异，包括感染率和致癌性。据我们所知，这将是首次对任何 HPV 变体进行全基因组分析。该提案的具体目标是将欧洲 HPV16 变种与两个非洲 HPV16 变种组（非洲 1 和非洲 2）以及亚裔美国人变种组进行比较。中心假设是，种族相关变异在感染性和致癌性方面存在机械差异，并且这些差异在与变异相关的种族背景个体的上皮组织中尤其严重。我们将围绕三个具体目标开展这些研究：具体目标 1：调查种族特异性 HPV16 变体致癌倾向的差异。具体目标 2：比较 HPV16 变种种族特异性角质形成细胞的感染性。具体目标 3：确定导致 HPV16 变种种族特异性生物学差异的遗传决定因素。