Identification and Regulation of RNA Modification by HIV infection and Methamphetamine

HIV感染和甲基苯丙胺对RNA修饰的鉴定和调控

基本信息

批准号：
10343670
负责人：
TARIQ M RANA
金额：
$ 61.59万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343670
关键词：
AIDS/HIV problem Address Affect Behavioral Binding Sites Biochemical Brain Brain Diseases CD4 Positive T Lymphocytes Cell physiology Complex Cytoplasm Data Development Disease Enzymes Flaviviridae Frequencies Gene Expression Regulation Genes Genetic Transcription Genome HIV HIV Infections HIV-1 Hepatitis C Human Immune Immune System Diseases Immune response Immune system Immunologics In Vitro Individual Infection Lead Life Cycle Stages Location Malignant Neoplasms Maps Mass Spectrum Analysis Messenger RNA Methamphetamine Methods Methylation Methyltransferase Modeling Modification Molecular Neurocognitive Nucleotides Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Play Post-Transcriptional Regulation Publishing RNA RNA Binding RNA Splicing RNA Viruses RNA metabolism Rana Regulation Reporting Role Site Specificity T-Lymphocyte Transcript Translations Viral Viral Pathogenesis Virus Virus Diseases Virus Replication ZIKV infection epitranscriptome epitranscriptomics experimental study immune activation immune function insight methamphetamine exposure methamphetamine use methylome mutant neurogenesis pathogen programs protein complex stem cell differentiation substance use success transcriptome viral RNA

项目摘要

PROJECT SUMMARY Post-transcriptional gene regulation by RNA modification is an emerging concept because a diverse set of modified nucleotides are found in mRNA sequences. The overall objective of this proposal is to delineate the molecular and cellular mechanisms by which HIV-1 infection and methamphetamine (MA) alter host transcriptional and translational programs to cause dysfunction of immune system. Our central hypothesis is that HIV-1 infection and use of MA alter the dynamics of the viral and host epitranscriptomes to regulate host-pathogen interactions. Recent findings from the Rana lab support this notion by showing that HIV-1 infection has profound effects on the topology and function of methylated RNAs of both viral and human RNAs. m6A abundance in HIV-1 RNA is controlled by the host methyltransferases METTL3 and METTL14 and the demethylases ALKBH5 and FTO. However, fundamental and critical questions regarding epitranscriptome regulation and its effects on HIV-1 pathogenesis remain to be addressed. To carry out these studies, we developed in vitro infection models as well as biochemical and functional characterization of RNA modifying complexes. Our project has three specific aims: Aim 1: Define the dynamics and mapping of viral and host RNA modifications by HIV infection and methamphetamine (MA) exposure. Aim 2: Determine how RNA modifications influence HIV-1 pathogenesis. Aim 3: Determine the dynamics and specific functions of RNA modifying machinery. Successful completion of these aims will significantly enhance our understanding of the epitranscriptomic regulation of gene expression caused by HIV infection. In addition, these results will provide fundamental understanding of the molecular mechanisms that are altered by MA use leading to immune dysfunctions.

项目概要通过 RNA 修饰进行转录后基因调控是一个新兴概念，因为在 mRNA 序列中发现了不同的修饰核苷酸组。本次活动的总体目标该提案旨在描述 HIV-1 感染和感染的分子和细胞机制甲基苯丙胺 (MA) 改变宿主转录和翻译程序，导致免疫系统功能障碍。我们的中心假设是 HIV-1 感染和 MA 的使用改变病毒和宿主表观转录组的动态来调节宿主病原体互动。 Rana 实验室的最新研究结果支持了这一观点，表明 HIV-1 感染对病毒和病毒的甲基化RNA的拓扑结构和功能都有深远的影响人类RNA。 HIV-1 RNA 中的 m6A 丰度由宿主甲基转移酶控制 METTL3 和 METTL14 以及去甲基酶 ALKBH5 和 FTO。然而，基本和关于表观转录组调控及其对 HIV-1 发病机制影响的关键问题仍有待解决。为了进行这些研究，我们开发了体外感染模型以及 RNA 修饰复合物的生化和功能表征。我们的项目具有三个具体目标：目标 1：定义病毒和宿主 RNA 的动力学和图谱 HIV 感染和甲基苯丙胺 (MA) 暴露造成的改变。目标 2：确定如何 RNA 修饰影响 HIV-1 发病机制。目标 3：确定动态和具体 RNA修饰机制的功能。这些目标的成功完成将显着增强我们对基因表达表观转录调控的理解艾滋病毒感染。此外，这些结果将提供对分子生物学的基本理解。 MA 使用改变的机制导致免疫功能障碍。