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: 8734379
• 负责人: Fenyong Liu
• 金额: $ 39.13万
• 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/8734379
• 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; 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; public health relevance; 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（由申请方提供）：口腔感染是人巨细胞病毒（HCMV）传播的重要途径。HCMV感染也是艾滋病患者口腔疾病的最常见原因之一。了解口腔粘膜以及口腔其他部位HCMV感染的机制将为开发治疗和预防HCMV相关口腔疾病的新药和新策略提供见解。 本研究的目的是研究口腔粘膜中HCMV染色质修饰及其在病毒感染中的作用。我们实验室最近的研究表明，在人类原代口腔细胞和组织培养物中，HCMV染色质中发现了表观基因组修饰，包括甲基化引起的组蛋白尾部变化。此外，初步研究表明，特定的病毒蛋白质影响表观遗传修饰 这些修饰中的一些特异性地调节HCMV生产性感染所需的病毒基因表达。 在拟议研究的初始部分，我们将筛选一组缺失单个病毒开放阅读框（ORF）的HCMV突变体，以分离表现出改变的病毒染色质修饰的突变体，并鉴定对口腔粘膜中HCMV染色质特异性修饰重要的病毒决定簇。然后将进行实验以研究所鉴定的病毒染色质修饰在调节病毒基因转录和支持病毒感染口腔细胞中的作用。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物相互作用来调节特定的HCMV染色质修饰，以促进口腔中的HCMV感染。这些研究将导致识别病毒的决定因素，重要的HCMV染色质修饰和病毒感染口腔粘膜。此外，我们的研究将探讨HCMV如何在口腔粘膜中复制，以及HCMV编码的决定簇如何调节HCMV染色质修饰并支持口腔粘膜中的病毒感染。我们的研究结果将提供深入了解 本研究旨在阐明口腔粘膜中HCMV感染的机制，并为口腔中HCMV的传播和感染的治疗和预防提供新的策略。