Regulation and Function of Human Polyomavirus circular RNAs

人多瘤病毒环状RNA的调控和功能

• 批准号: 10598409
• 负责人: Richard C Wang
• 金额: $ 21.75万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-08 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10598409
• 关键词: Activator Appliances; Affect; Applications Grants; Binding Proteins; Biology; Candidate Disease Gene; Cells; Co-Immunoprecipitations; Code; Collaborations; Complex; DNA Tumor Viruses; DNA Virus Infections; DNA Viruses; Data; Diagnostic; Disease; Elements; Future; Genes; Genetic Transcription; Genome; Goals; Human; Human Papillomavirus; In Vitro; Knowledge; Mediating; Merkel Cells; Merkel cell carcinoma; MicroRNAs; Modeling; Modification; Mutagenesis; Oncoproteins; Pathogenesis; Pathway interactions; Patients; Physiological; Play; Polymerase; Polyomavirus; Polyomavirus Infections; Polyomaviruses Middle T Proteins; Property; Proteins; Qualifying; RNA; RNA Splicing; RNA metabolism; Regulation; Resistance; Role; Signal Transduction; Site-Directed Mutagenesis; Small Interfering RNA; Therapeutic; Tissues; Trans-Activators; Transactivation; Translating; Translations; Viral; Viral Genome; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; circular RNA; ds-DNA; experimental study; high risk; human disease; knock-down; novel; novel diagnostics; pathogen; response; success; trait; transcriptome; tumor; virology

An increasing number of circular RNAs (circRNAs) have been found to be expressed by both viruses and human host cells during viral infection, yet the physiological significance of most circRNAs remains unclear. Our long-term goal is to use human polyomaviruses (HPyVs) to understand the regulation and function of circRNAs and to leverage this knowledge towards developing new diagnostics and treatments for viral diseases. We propose that many viral circRNAs function as coding RNAs that have distinct properties from linear RNAs spliced from the same gene. Specifically, our central hypothesis is that Merkel cell polyomavirus and trichodysplasia spinulosa polyomavirus encodes circular ALTO RNAs, circALTOs, that are translated to ALTO, which then modulates transcription in infected host cells. This model is based on preliminary studies showing that both MCPyV and TSPyV early regions efficiently generate circALTO, which are translated into ALTO protein in vitro. MCPyV circALTO functions as a transcriptional transactivator that can induce the transcription of multiple genes and pathways that have previously been implicated in DNA virus infections. We further demonstrate that a miRNA expressed from the MCPyV early region, miR-M1, negatively regulates circALTO and ALTO levels. Extending and validating this model would represent a ground-breaking advance in our understanding of circRNA function and regulation. This proposal will be organized into two aims: 1) Identify the factors that regulate the formation of MCPyV circALTO and its inhibition by the MCPyV miR-M1 miRNA and determine how these factors impact viral replication and persistence; 2) Determine how MCPyV ALTO modulates host cell transcription and whether ALTO’s effects on transcription are conserved in TSPyV. We will collaborate with virologists with expertise in polyomaviruses and miRNA biology to complete the proposed aims. Completion of this proposal will not only expand the relevance of circRNAs in virology and cell signaling but also significantly advance our understanding of the pathogenesis of human polyomaviruses.

发现越来越多的圆形RNA（CIRCRNA）由病毒和 病毒感染期间的人类宿主细胞，但大多数CircrNA的生理意义尚不清楚。 我们的长期目标是使用人类多瘤病毒（HPYV）来了解 circrnas并利用这些知识来开发新的诊断和teral for。 疾病。我们提出许多病毒circrnas作为编码 从同一基因剪接的线性RNA。 多瘤病毒和毛状腺肿症脊柱多瘤病毒编码圆形中音RNA，circaltos 被翻译成Alto，然后调节感染的宿主细胞中的转录。 初步研究表明，MCPYV和TSPYV早期区域都会产生Circalto，这 在体外翻译成中心蛋白。 可以诱导与DNA有关的多个基因和途径的转录 病毒感染。 负责调节Circalto和Alto级别。 我们对CIRCRNA功能和监管的开创性进步。 组织为两个目的：1）确定将MCPYV Circalto及其形成的因素 MCPYV miR-M1 miRNA抑制，并确定因素如何影响病毒复制和 持久性； 2）确定McPyv Alto如何模块化宿主细胞转录以及Alto的效果 在TSPYV中，转录是保守的。 多瘤病毒和miRNA生物学以完成该提案的旨意。 仅扩大了培训和细胞信号的相关性，但也显着提高了我们的 了解人多瘤病的发病机理。