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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.

项目摘要通过RNA修饰的转录后基因调控是一个新兴的概念，因为在mRNA序列中发现了不同的修饰核苷酸组。本报告的总体目标这项研究的目的是阐明HIV-1感染和甲基苯丙胺（MA）改变宿主的转录和翻译程序，免疫系统功能紊乱。我们的中心假设是HIV-1感染和使用MA 改变病毒和宿主表转录组的动力学以调节宿主-病原体交互. Rana实验室最近的研究结果支持了这一观点，表明HIV-1 感染对病毒和哺乳动物的甲基化RNA的拓扑结构和功能都有深远的影响。人类RNA。HIV-1 RNA中m6 A丰度受宿主甲基转移酶控制胃L3和胃L14以及脱甲基酶ALKBH 5和FTO。然而，基本的和关于表转录组调控及其对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修饰复合物的生物化学和功能表征。我们的项目目标1：定义病毒和宿主RNA的动力学和映射艾滋病毒感染和甲基苯丙胺（MA）暴露的变化。目标2：确定如何 RNA修饰影响HIV-1发病机制。目标3：确定动力学和具体 RNA修饰机器的功能。这些目标的成功实现将大大增强我们对基因表达的表转录调控的理解，艾滋病毒感染。此外，这些结果将提供对分子的基本理解， MA使用改变了导致免疫功能障碍的机制。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Detection of N6-methyladenosine in SARS-CoV-2 RNA by methylated RNA immunoprecipitation sequencing.

DOI：
10.1016/j.xpro.2021.101067
发表时间：
2022-03-18
期刊：
STAR protocols
影响因子：
0
作者：
Li N;Rana TM
通讯作者：
Rana TM

METTL3 regulates viral m6A RNA modification and host cell innate immune responses during SARS-CoV-2 infection.

METTL3调节SARS-COV-2感染期间的病毒M6A RNA修饰和宿主细胞先天免疫反应。

DOI：
10.1016/j.celrep.2021.109091
发表时间：
2021-05-11
期刊：
Cell reports
影响因子：
8.8
作者：
Li N;Hui H;Bray B;Gonzalez GM;Zeller M;Anderson KG;Knight R;Smith D;Wang Y;Carlin AF;Rana TM
通讯作者：
Rana TM

Regulation of antiviral innate immunity by chemical modification of viral RNA.