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：
9320796
负责人：
Craig M Meyers
金额：
$ 29.1万
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/9320796
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 DNA Sequence Alteration Epithelial Ethnic Origin Ethnic group European Exhibits Family Founder Effect Gene Proteins Genes Genetic Genetic Determinism Genome Genotype 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 Oncogenic Population Population Study Positioning Attribute Predisposition Prevalence Production Public Health Race Research Resources Tissues Variant Viral Virus cancer health disparity carcinogenicity epidemiologic data ethnic difference gene product genome analysis keratinocyte mRNA Differential Displays prototype public health relevance tissue culture tool whole genome

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在全球范围内鉴定出相对于原型基因组的主要衣壳蛋白基因的差异少于2％。流行病学和临床数据的体系已出现了与宫颈肿瘤的临床进展和攻击性差异的HPV16变体组。尽管特定的患病率因地理而有所不同，但在全球范围内检测到来自所有主要HPV16变体谱系的代表性变体。特定HPV变体的感染和致癌性在地理上似乎变化，并且随研究人群的种族起源而变化。变体谱系的最大预测因子是种族。变体，尤其是那些与非洲或亚洲血统相关的人群具有更大的持久性倾向。已经尝试将HPV16变体展示的临床图片差异与生物学和生命周期相关联病毒的。但是，这些研究中的大多数已经分别分析了病毒的特定基因或区域的功能，例如E6基因产物或上部调节区域。为了明确评估因果遗传效应，需要进行全基因组分析。没有与病毒生命周期和感染性有关的全基因组研究，以及与种族有关。我们在体外重现完整病毒生命周期的能力，包括产生感染性病毒，使我们有能力提出对HPV16变体的全基因组分析。我们还拥有研究HPV16变体与种族特异性宿主组织的相互作用的工具和专业知识。我们的长期目标是使用全基因组分析（包括感染率和致癌性）了解HPV变体的种族差异。据我们所知，这将是任何HPV变体的首次全基因组分析。该提案的具体目标是将欧洲HPV16变体与两个非洲HPV16变体组（非洲-1和非洲-1和非洲2）和亚裔美国人变体组进行比较。中心假设是种族相关的变体在感染性和致癌性方面有机学上的差异，并且这些差异在与该变体相关的种族背景个体的上皮组织中尤其急剧。我们将以三个特定目的进行这些研究：具体目标1：研究种族特异性HPV16变体的致癌倾向的差异。具体目标2：比较HPV16变体的感染性种族特异性角质形成细胞。特定目的3：确定负责HPV16变体的种族特异性生物学差异的遗传决定因素。