Epstein-Barr Virus-Enhanced Tumor Progression

Epstein-Barr 病毒增强的肿瘤进展

基本信息

批准号：
7802081
负责人：
RONA S SCOTT
金额：
$ 28.39万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7802081
关键词：
Address Affect Base Pairing Biological Biology Biopsy Carrier State Cell physiology Cells Central Nervous System Lymphoma Clinical Clonal Evolution Clonal Expansion Clonality Data Disease Disease Progression Epigenetic Process Episome Epithelial Cells Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr pathogenesis Equilibrium Evolution Future Gene Expression Gene Silencing Genes Genetic Recombination Genome Genomics Growth Heterogeneity Hodgkin Disease Human Human Herpesvirus 4 Human Virus In Vitro Individual Infection Introns Laboratories Large-Cell Immunoblastic Lymphoma Latent Virus Length Lesion Life Link Lymphoma Lymphoproliferative Disorders Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Measures Mediator of activation protein Membrane Proteins Memory Methylation Modeling Modification Molecular Molecular Virology Nasopharynx Carcinoma Natural Killer Cells Nature Nose Oncogene Proteins Pathway interactions Pattern Phenotype Population Process Proteins RNA Splicing Research Research Personnel Role Serological Signal Transduction Staging Stomach Carcinoma System Terminal Repeat Sequences Testing Therapeutic Thymic Carcinoma Time Transcript Transplantation Tumor Initiators Undifferentiated Viral Viral Markers Virion Virus Virus Diseases base carcinogenesis cell growth clinical material directed attention established cell line human FRAP1 protein imprint in vivo laser capture microdissection leiomyosarcoma mTOR protein neoplastic cell pathogen prognostic programs protein expression public health relevance tumor tumor progression tumorigenesis viral DNA

项目摘要

DESCRIPTION (provided by applicant): Among human viruses etiologically linked to human cancer, the Epstein Barr virus (EBV) is unusual because of the diverse assortment of malignancies with which it is associated, if only sporadically. Our long term objective is to understand how a ubiquitous and persistent viral pathogen that normally achieves a lasting rapport with its host becomes pathogenic years after primary infection. Emerging possibilities that more fully acknowledge EBV opportunism in the context of the life-long carrier state include viral reactivation with entry into cells made more prone to infection and EBV-enhanced malignant progression by pre-existing molecular alterations. Here, we examine EBV tumorigenesis within a new conceptual framework of chance infection of neoplastic cells by virus endogenous to the host, with possible viral DNA loss from some tumors after EBV contribution to growth has been made. Aim 1 will use the pattern of EBV distribution and clonality in human tumor biopsies, as discerned by laser capture microdissection and single cell quantitative PCR, to establish a time frame for infection, subsequent clonal evolution, and EBV DNA loss. Aim 2 will determine how variably reiterated EBV terminal repeat (TR) sequences, comprising the first intron of the LMP2A gene, govern expression levels of this EBV oncoprotein. With TRs a commonly employed viral marker of tumor clonality, information obtained may implicate TR number per se in a process of cell selection that drives the transition from polyconal infection of a few tumor cells to monoclonal outgrowth of a subset with the highest LMP2A expression. Aim 3 will define the genomics of EBV redundancy and loss. In a newly devised in vitro system of transient infection, we will establish whether EBV transit through a cell produces epigenetic gene silencing as a component of the multistep process of carcinogenesis. The public health relevance of this research is that it will answer fundamental biological questions on the nature of EBV's erratic association with an ever expanding array of human tumors. Does EBV have the capability to initiate every tumor in which it is found as currently presupposed on the basis of EBV clonality or does it contribute instead to late stages of disease, entering cells more prone to infection and malignant progression by prior molecular mishaps? The information gained will further elucidate EBV's role in human cancer, its prognostic significance, and future therapeutic approaches.

描述（由申请人提供）：在与人类癌症的人类病毒中，爱泼斯坦Barr病毒（EBV）是不寻常的，因为与之相关的恶性肿瘤有多种多样，即使只是偶然地相关。我们的长期目标是了解通常与宿主持续融洽的无处不在的病毒病原体如何成为原发性感染后的致病年份。在终生载体状态下，更充分地认识到EBV机会主义的新兴可能性包括病毒重新激活，进入细胞的可能性更容易受到感染和EBV增强的恶性进展，这是通过预先存在的分子改变。在这里，我们在一个新的概念框架内检查了EBV肿瘤发生在宿主内源性的肿瘤细胞偶然感染的新概念框架内，在EBV对生长贡献后，可能会因某些肿瘤的病毒DNA损失。 AIM 1将利用人类肿瘤活检中的EBV分布和克隆性模式，通过激光捕获显微解剖和单细胞定量PCR辨别，以建立感染的时间范围，随后的克隆演化和EBV DNA损失。 AIM 2将确定如何多样地重申EBV末端重复（TR）序列，包括LMP2A基因的第一个内含子，控制该EBV癌蛋白的表达水平。对于TRS，在细胞选择过程中，获得的信息通常牵涉到TR数量，可能暗示TR数量，该过程驱动了从几个肿瘤细胞的多结膜感染到亚基的单克隆生长的过渡，并具有最高的LMP2A表达。 AIM 3将定义EBV冗余和损失的基因组学。在新设计的瞬时感染体外系统中，我们将确定通过细胞的EBV转运是否会产生表观遗传基因沉默，这是癌变多步过程的组成部分。这项研究的公共卫生相关性是，它将回答有关EBV与不断扩大的人类肿瘤的不稳定联系的基本生物学问题。 EBV是否有能力启动所有根据EBV克隆性为前提所见的肿瘤，还是会导致疾病的晚期，使细胞更容易受到先前的分子不良的感染和恶性进展？获得的信息将进一步阐明EBV在人类癌症中的作用，其预后意义以及未来的治疗方法。