Gammaherpesvirus interactions with host tumor suppressor p53

伽马疱疹病毒与宿主肿瘤抑制因子 p53 的相互作用

基本信息

批准号：
8696558
负责人：
James Craig Forrest
金额：
$ 36万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-04 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696558
关键词：
Address Adult Animal Model Animals Antiviral Agents B-Lymphocyte Subsets Biological Models Cell Differentiation process Cell Proliferation Cells Cellular Tropism Chronic DNA Tumor Viruses DNA Viruses Data Defense Mechanisms Disease Gene Deletion Gene Expression Genetic Genetic Transcription Goals HIV Homologous Gene Human Human Herpesvirus 4 Human Herpesvirus 8 Immune response Incidence Individual Infection Lymphocyte Malignant Neoplasms Mediating Mus Organ Transplantation Pathogenesis Pathway interactions Patients Preclinical Testing Protein p53 Proteins Publishing Resistance Risk Rodent Role Solid System Testing Therapeutic Intervention Transcriptional Regulation Transplant Recipients Tumor Suppressor Proteins Viral Viral Genes Viral Load result Viral Proteins Virus Virus Diseases Work base cell type gammaherpesvirus high risk in vivo insight latency-associated nuclear antigen latent infection metaplastic cell transformation mutant neoplastic novel novel therapeutic intervention novel virus pathogen prevent public health relevance research study response therapeutic target tissue culture tumorigenesis virus genetics

项目摘要

DESCRIPTION (provided by applicant): Gammaherpesviruses (GHVs) establish lifelong chronic infections that place the host at risk for numerous cancers. During chronic infection, GHVs express viral gene products that stimulate host-cell proliferation and differentiation, processes thought to facilitate long-term latent persistence and contribute to tumorigenesis. However, GHVs are not acutely transforming, and cancer is rare given the high incidence of infection among adult humans, estimated at more than 90% for Epstein-Barr virus. This suggests that host cells are equipped with an intrinsic resistance to GHV-driven proliferation and cellular immortalization, but few host molecules capable of mediating this effect are known and whether these molecules functionally restrict GHV persistence and disease in vivo has not been established. Experiments described in this proposal seek to identify and confirm the in vivo relevance of host molecules with the capacity to limit GHV chronic infection and disease in three Specific Aims. Based on preliminary studies that employed murine gammaherpesvirus-68 (MHV68) infection of mice, experiments described in Specific Aim 1 test the function of host tumor suppressor protein p53, a critical molecule for preventing neoplastic disease, as an innate barrier to MHV68 latent persistence and cellular transformation. Experiments presented in Specific Aim 2 seek to define mechanisms whereby p53 limits MHV68 latent infection. Experiments in Specific Aim 3 will provide the first in vivo test of the long- standing hypothesis that latency-associated nuclear antigen, a conserved GHV disease determinant capable of inhibiting p53 functions in tissue culture, is necessary to overcome a p53-mediated restriction to enable long- term latent infection. These experiments harness the powerful mouse and MHV68 genetic systems to address a question that is fundamental to our understanding of the GHV-host dynamic. Further, we anticipate that results of this work will inform new therapeutic approaches aimed at enhancing p53 functions to limit or prevent GHV-related cancers, especially in high-risk patients such as HIV-infected individuals or solid-organ transplant recipients.

描述（由申请人提供）：伽玛疱疹病毒（GHV）会造成终生慢性感染，使宿主面临多种癌症的风险。在慢性感染期间，GHV 表达刺激宿主细胞增殖和分化的病毒基因产物，这一过程被认为促进长期潜伏持续并有助于肿瘤发生。然而，GHV 并没有急剧转变，而且考虑到成年人感染率很高（估计 Epstein-Barr 病毒的感染率超过 90%），癌症也很罕见。这表明宿主细胞具有对 GHV 驱动的增殖和细胞永生化的内在抵抗力，但很少有能够介导这种效应的宿主分子，并且这些分子是否在功能上限制 GHV 持久性和体内疾病尚未确定。本提案中描述的实验旨在识别和确认宿主分子在三个特定目标中限制 GHV 慢性感染和疾病的体内相关性。基于使用小鼠伽马疱疹病毒 68 (MHV68) 感染小鼠的初步研究，具体目标 1 中描述的实验测试了宿主肿瘤抑制蛋白 p53 的功能，p53 是预防肿瘤疾病的关键分子，作为 MHV68 潜在持久性的先天屏障，并且细胞转化。具体目标 2 中提出的实验试图确定 p53 限制 MHV68 潜伏感染的机制。具体目标 3 中的实验将首次对长期存在的假设进行体内测试，即潜伏相关核抗原（一种能够抑制组织培养中 p53 功能的保守 GHV 疾病决定因素）对于克服 p53 介导的限制是必要的，从而使长期潜伏感染。这些实验利用强大的小鼠和 MHV68 遗传系统来解决一个对于我们理解 GHV 宿主动态至关重要的问题。此外，我们预计这项工作的结果将为旨在增强 p53 功能的新治疗方法提供信息，以限制或预防 GHV 相关癌症，特别是在高危患者中，例如 HIV 感染者或实体器官移植受者。