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Characterizing the role of cellular differentiation in productive papillomavirus amplification

表征细胞分化在生产性乳头瘤病毒扩增中的作用

基本信息

批准号：
10347352
负责人：
Koenraad Van Doorslaer
金额：
$ 15.35万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-08 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10347352
关键词：
3-Dimensional Accounting Address Area Basal Cell Biological Biological Models CRISPR/Cas technology Calcium Catalogs Cell Differentiation process Cell division Cell physiology Cells Chromosomes DNA DNA biosynthesis Development Dropout Early Diagnosis Ensure Epidermis Epithelial Epithelial Cells Equilibrium Foundations Future Gene Expression Genes Genetic Genetic Screening Genetic Transcription Genome Genomic approach Goals HPV-High Risk Head and Neck Cancer Human Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 In Vitro Incidence Individual Infection Intervention Knock-out Knowledge Late Gene Transcriptions Length Life Cycle Stages Link Malignant Neoplasms Malignant neoplasm of cervix uteri Mitotic Oncogenic Oropharyngeal Squamous Cell Carcinoma Papillomavirus Pathway interactions Phase Physiological Physiological Processes Population Process Production Risk Factors Role Sex Behavior Side Stratification Structural Genes Structure Supporting Cell System Tissues Tonsil Vaccination Viral Viral Genes Viral Genome Viral Oncogene Virion Virus Virus Activation Virus Replication Work genome-wide human papilloma virus oncogene improved insight keratinocyte keratinocyte differentiation malignant oropharynx neoplasm oral cavity epithelium pathogen screening screening program self-renewal spatiotemporal tissue culture transcriptome transmission process tumor viral DNA viral transmission virus host interaction

项目摘要

Project Summary/Abstract Human papillomavirus (HPV) infections are responsible for a staggering 5% of all cancers worldwide. In the developed world, these infections cause an increasing number of oropharyngeal cancers. An estimated third of all oropharyngeal squamous cell carcinomas (OPSCC) are caused by HPV infection. Sexual behavior is a potent risk factor for HPV(+)-OPSCC, suggesting that a better understanding of viral transmission is critical. The viral lifecycle, specifically genome amplification and virion production, is intricately linked with cellular differentiation. We will characterize cellular genes that regulate the productive stages of the viral lifecycle. We will use HPV16 positive tonsillar epithelium equivalents grown in three-dimensional (3D) organotypic raft culture to recapitulate the effects of cellular differentiation on the viral lifecycle. Using this model system, we will use high-throughput approaches to identify cellular genes that regulate the productive viral lifecycle. Specifically, we aim to 1) identify how the expression of specific human genes co-varies with distinct phases in the viral lifecycle; 2) use a genetic screening approach to characterize cellular genes that are required for late gene transcription. The details regulating the late, productive stage of the viral lifecycle are not understood. Understanding the interplay between viral and cellular genes regulating cellular differentiation will lead to an improved basic biological knowledge of the papillomavirus life cycle and towards the development of possible interventions for HPV infections and associated cancers.

项目总结/摘要人乳头瘤病毒（HPV）感染是全球所有癌症的5%。在在发达国家，这些感染导致口咽癌的数量不断增加。据估计，所有的口咽鳞状细胞癌（OPSCC）都是由HPV感染引起的。性行为是一种 HPV（+）-OPSCC的潜在危险因素，表明更好地了解病毒传播至关重要。病毒的生命周期，特别是基因组扩增和病毒体的产生，与细胞内的分化我们将描述调节病毒生命周期生产阶段的细胞基因。我们将使用在三维（3D）器官型筏中生长的HPV 16阳性扁桃体上皮等同物培养以概括细胞分化对病毒生命周期的影响。利用这个模型系统，我们将使用高通量的方法来确定调节生产性病毒生命周期的细胞基因。具体来说，我们的目标是1）确定特定人类基因的表达如何与不同的阶段共同变化，病毒生命周期; 2）使用遗传筛选方法来表征晚期所需的细胞基因基因转录调节病毒生命周期的晚期、多产阶段的细节尚不清楚。了解病毒和调节细胞分化的细胞基因之间的相互作用将导致提高对乳头瘤病毒生命周期的基本生物学知识， HPV感染和相关癌症的干预措施。