Virus Host Interactions that Regulate Translation in Cells Infected with HSV-1

调节 HSV-1 感染细胞翻译的病毒宿主相互作用

基本信息

批准号：
8675699
负责人：
Ian J Mohr
金额：
$ 38.07万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-16 至 2015-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675699
关键词：
7-methylguanosine triphosphate Affect Alleles Back Binding Binding Proteins Biological Models Brain Cells Complex Disease Encephalitis Epithelial Eye diseases Gene Expression Genes Genetic Genetic Translation Growth Herpesviridae Herpesvirus 1 Human Immune system Immunocompetent Immunocompromised Host Individual Infection Insulin Investigation Ions Life Mutation Newborn Infant Peptide Initiation Factors Phenotype Phosphorylation Phosphotransferases Post-Translational Protein Processing Process Production Property Protein Biosynthesis Protein Complex Subunit Protein Isoforms Proteins Proteomics RNA Cap-Binding Proteins Ribosomes Signal Pathway Signal Transduction Simplexvirus Skin Therapeutic Intervention Transcript Translations Viral Viral Genes Viral Proteins Virus Virus Replication Work design human FRAP1 protein human disease mRNA capping mutant neonate obligate intracellular parasite polypeptide prevent protein complex reactivation from latency repaired research study translation factor virus host interaction

项目摘要

A critical step in mRNA translation involves the recruitment of the 40S ribosome subunit to the 5' end of capped transcripts. Typically, an ensemble of multi-subunit translation initiation factors executes this task. Viruses provide attractive model systems to study this fundamental process, as they are obligate intracellular parasites, completely dependent upon the protein synthesis machinery resident in their hosts. As mRNA translation is necessary for their replication, viruses are proficient in manipulating not only the host cell translational machinery, but also effectively commandeer the cellular signaling pathways that regulate protein synthesis. This investigation concentrates on Herpes simplex virus-1 (HSV-1), a neurotrophic herpesvirus whose productive replication is responsible for a spectrum of human diseases ranging from self- limiting epithelial sores, severe ocular disease and life threatening encephalitis in immunocompetent hosts to disseminated disease in neonates and immunocompromised individuals. Our long - term objective is to understand how HSV-1 successfully engages and controls the cellular protein synthesis apparatus by both altering and remodeling translation initiation factor complexes required for the production of both cellular and viral polypeptides. As this process is of vital importance for reactivation from latency and vegetative viral growth, our analysis is likely to uncover new targets for potential therapeutic intervention. We specifically propose to i) understand the mechanism(s) whereby cellular translation factor complexes are altered as a result of HSV-1 infection; ii) investigate how the cellular translation repressor 4E- binding protein-1 is controlled in HSV-1 infected cells; and iii) determine how HSV-1 manipulates the cellular kinase mTOR to properly control viral protein synthesis.

mRNA翻译的关键步骤涉及将40S核糖体亚基募集到上限转录本的5端。通常，多工资翻译起始因子的合奏会执行此任务。病毒提供了有吸引力的模型系统来研究这一基本过程，因为它们是务实的细胞内寄生虫，完全取决于其宿主中的蛋白质合成机械。由于mRNA翻译对于它们的复制是必需的，因此病毒不仅精通宿主细胞平移机制，而且还可以有效地指挥调节蛋白质合成的细胞信号传导途径。这项研究集中在单纯疱疹病毒1（HSV-1）上，这是一种神经营养性疱疹病毒，其富有生产力的复制是造成人类疾病的范围，从自我限制的上皮疮，严重的眼部疾病，严重的眼部疾病和在免疫性疾病中造成毒性疾病和昆虫症中造成的障碍的脑炎和肿瘤中的脑炎症状症状。我们的长期目标是了解HSV -1如何通过改变和重塑的翻译起始因子复合物既成功地接合和控制细胞蛋白的合成设备。由于此过程对于从潜伏期和营养病毒生长中重新激活至关重要，因此我们的分析可能会发现潜在的治疗干预措施的新靶标。我们特别建议i）了解由于HSV-1感染而改变了细胞翻译因子复合物的机制； ii）研究如何在HSV-1感染的细胞中控制细胞翻译抑制剂4E-结合蛋白-1； iii）确定HSV-1如何操纵细胞激酶MTOR以正确控制病毒蛋白合成。