Human cytomegalovirus chromatin modifications in oral infection

口腔感染中的人巨细胞病毒染色质修饰

• 批准号: 9026715
• 负责人: Fenyong Liu
• 金额: $ 3.05万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026715
• 关键词: AIDS-Related Disorder; Acquired Immunodeficiency Syndrome; Affect; Animal Model; Biological Models; Cell Nucleus; Cells; Chromatin; Chromatin Structure; Collection; Complex; Cytomegalovirus; Cytomegalovirus Infections; DNA-Directed RNA Polymerase; Development; Disease; Early Gene Transcriptions; Epigenetic Process; Exclusion; Exhibits; Gene Deletion; Gene Expression; Genes; Genetic Transcription; Genome; Growth; Health; Herpesviridae; Histones; Human; Immediate-Early Genes; In Vitro; Infection; Laboratories; Late Gene Transcriptions; Lead; Mediating; Methylation; Modeling; Modification; Mouth Diseases; Nucleosomes; Open Reading Frames; Oral; Oral cavity; Oral mucous membrane structure; Patients; Pharmaceutical Preparations; Phase; Polycomb; Post-Translational Protein Processing; Prevention; Proteins; Regulation; Reporting; Research; Role; Route; Staging; System; Tail; Therapeutic Agents; Tissue Model; Tissues; Transcript; Transcription Elongation; Transcriptional Activation; Viral; Viral Genes; Viral Physiology; Viral Proteins; Virus Diseases; Virus Inactivation; chromatin modification; congenital infection; epigenomics; histone modification; insight; keratinocyte; mutant; novel strategies; oral infection; oral tissue; pathogen; promoter; research study; tissue/cell culture; transmission process

DESCRIPTION (provided by applicant): Oral infection represents an important route of human cytomegalovirus (HCMV) transmission. HCMV infection is also among the most common causes of oral diseases associated with AIDS patients. Understanding the mechanism of HCMV infection in oral mucosa as well as other parts of the oral cavity will provide insight into developing new drugs and novel strategies for treatment and prevention of HCMV-associated oral diseases. The objective of the proposed research is to study HCMV chromatin modifications and their roles in viral infection in oral mucosa. Recent studies in our laboratory have shown that epigenomic modifications, including histone tail changes by methylation, have been found in HCMV chromatin in human primary oral cell and tissue cultures. Furthermore, preliminary studies have suggested that specific viral proteins affect the epigenetic modifications of viral chromatin, and that some of these modifications specifically modulate the expression of viral gene expression required for HCMV productive infection. In the initial part of the proposed study, we will screen a collection of HCMV mutants with deletion of a single viral open reading frame (ORF) to isolate mutants that exhibit altered viral chromatin modifications and to identify viral determinants important for specific modifications of HCMV chromatin in oral mucosa. Experiments will then be carried out to study the roles of the identified modifications of viral chromatin in regulating viral gene transcription and supporting viral infection in oral cells. Furthermore, experiments will also be carried out to investigate how the viral determinants modulate specific HCMV chromatin modifications by interacting with the epigenetic remodeling complexes in order to facilitate HCMV infection in oral cavity. These studies will lead to the identification of viral determinants important for HCMV chromatin modifications and for viral infection in oral mucosa. Furthermore, our studies will investigate how HCMV replicates in oral mucosa and how HCMV-encoded determinants function to modulate HCMV chromatin modifications and support viral infection in oral mucosa. Our results will provide insight into the mechanism of HCMV infection in oral mucosa and facilitate the development of novel strategies for treatment and prevention of the transmission as well as infection of HCMV in oral cavity.

描述(申请人提供)：口腔感染是人类巨细胞病毒(HCMV)传播的重要途径。人类巨细胞病毒感染也是与艾滋病患者相关的口腔疾病的最常见原因之一。了解口腔粘膜和口腔其他部位的巨细胞病毒感染机制，将为开发治疗和预防巨细胞病毒相关口腔疾病的新药和新策略提供新的思路。本研究的目的是研究人巨细胞病毒染色质修饰及其在口腔粘膜病毒感染中的作用。我们实验室最近的研究表明，在人类口腔原代细胞和组织培养物中，发现了包括组蛋白尾部甲基化在内的表观基因组修饰。此外，初步研究表明，特定的病毒蛋白影响表观遗传修饰 病毒染色质的表达，并且其中一些修饰专门调节产生巨细胞病毒感染所需的病毒基因表达。在拟议的研究的初始部分，我们将筛选一组缺失单个病毒开放阅读框架(ORF)的HCMV突变株，以分离表现出病毒染色质改变的突变株，并确定对口腔粘膜中HCMV染色质的特异性修饰至关重要的病毒决定因素。然后将进行实验，研究已确定的病毒染色质修饰在调节病毒基因转录和支持口腔细胞中病毒感染方面的作用。此外，还将进行实验，以研究病毒决定簇如何通过与表观遗传重塑复合体相互作用来调节特定的HCMV染色质修饰，以促进HCMV在口腔中的感染。这些研究将导致对HCMV染色质修饰和口腔粘膜病毒感染重要的病毒决定因素的鉴定。此外，我们的研究将探讨巨细胞病毒如何在口腔粘膜中复制，以及巨细胞病毒编码的决定簇如何调节巨细胞病毒染色质的修饰和支持口腔粘膜中的病毒感染。我们的结果将为我们提供对 研究人巨细胞病毒在口腔粘膜中的感染机制，并为开发新的治疗和预防口腔内人巨细胞病毒传播和感染的策略提供便利。