Structure of the HIV-1 Genome

HIV-1 基因组的结构

基本信息

批准号：
9919372
负责人：
Kevin M Weeks
金额：
$ 65.13万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919372
关键词：
Acylation Adopted Anti-Retroviral Agents Antiviral Agents Binding Bioinformatics Biological Chemicals Chemistry Communicable Diseases Communication Complex Computer software Data Development Drug Targeting Elements Environment Gene Expression Regulation Generations Genetic Code Genome Gold HIV HIV Genome HIV-1 Higher Order Chromatin Structure Hydroxyl Radical Individual Infection Laboratories Length Link Maps Massive Parallel Sequencing Measurement Measures Mediating Methods Modeling Molecular Conformation Monitor Nuclear Nucleocapsid Nucleotides Pathway interactions Pharmaceutical Preparations Primer Extension Proteins RNA RNA Binding RNA Probes RNA Viruses Regulatory Element Research Resolution Science Secondary Protein Structure Shapes Signal Transduction Site Structural Biologist Structural Protein Structure Technology Testing Therapeutic Uncertainty Viral Viral Genome Virion Virus Work automated analysis computerized data processing density design dimer drug development experimental study genome-wide genomic RNA innovation new technology novel particle platform-independent programs public health relevance single molecule software development three dimensional structure user friendly software user-friendly virus genetics

项目摘要

DESCRIPTION (provided by applicant): This project, focused on characterization of the three-dimensional structures of RNA molecules in biologically relevant environments, links broadly important problems in biomedical science. First, the human immunodeficiency virus (HIV) currently infects 35 million individuals globally with roughly 3 million new infections per year. Studies of the protein components of the virus have led to the development of multiple effective drugs, but additional effective antiretroviral agents are needed. In principle, the RNA genome itself is a compelling drug target. The conserved, functional motifs in the HIV-1 genomic RNA that we have identified - and elements that we will characterize as part of this proposal - have significant promise as novel targets and pathways for antiretroviral drug development. Second, the extraordinary density of information encoded in the higher-order structure of the HIV-1 RNA genome represents a key component of the genetic code, one that we understand poorly at present. This research program will enhance our understanding of the principles that govern RNA-mediated gene regulation. It will also advance our understanding of the organization and compaction of RNA virus genomes and will illuminate principles that apply to densely organized RNAs including lncRNAs, nuclear bodies, and other regulatory elements. Third, the SHAPE probing strategy, pioneered by our lab, yields quantitative but highly specific nucleotide-resolution information, and, therefore, we are now focusing on developing multiple, alternative, complementary strategies that specifically detect true through-space and higher-order interactions in RNA. Finally, throughout this project, we will create integrated strategies that meld multiple, complementary, experimentally concise, and physically accurate structure probing technologies with user-friendly data processing to make possible facile and comprehensive functional analyses of large RNAs in relevant cellular contexts by non-expert laboratories. Our collaborative team, consisting of HIV virologists, RNA structural biologists, and experts in bioinformatics, will tackle the following Aims: (1) Analyze the structure of complete HIV-1 genomes inside authentic virions using the genome-scale SHAPE-MaP strategy; (2) identify through-space interactions across the entire HIV-1 genome by large-scale, single-molecule, correlated chemical probing experiments; (3) comprehensively define the intra- and inter-molecular interactions that mediate the RNA interactome of packaged HIV-1 genomic RNAs; and (4) create robust platform-independent software for fully automated analysis of chemical probing experiments that specifically measure through-space interactions in RNA.

描述（由申请人提供）：该项目的重点是表征生物相关环境中 RNA 分子的三维结构，这是生物医学领域广泛重要的问题。首先，人类免疫缺陷病毒 (HIV) 目前感染了全球 3500 万人。每年大约有 300 万例新感染病例，对病毒蛋白质成分的研究导致了多种有效药物的开发，但还需要更多有效的抗逆转录病毒药物。原则上，RNA 基因组本身就是一种引人注目的药物。我们已经确定的 HIV-1 基因组 RNA 中的保守功能基序以及我们将作为该提案的一部分描述的元素，作为抗逆转录病毒药物开发的新靶点和途径具有重要前景。 HIV-1 RNA 基因组高阶结构中编码的信息代表了遗传密码的关键组成部分，而我们目前对这一组成部分了解甚少。这项研究计划将增强我们对 RNA 介导的基因调控原理的理解。它还将增进我们对组织和RNA病毒基因组的压缩，并将阐明适用于密集组织的RNA（包括lncRNA、核体和其他调控元件）的原理。第三，我们实验室首创的SHAPE探测策略可产生定量但高度特异性的核苷酸分辨率信息，并且，因此，我们现在专注于开发多种、替代、互补的策略，专门检测 RNA 中真实的空间和高阶相互作用。最后，在整个项目中，我们将创建融合多种、互补、实验简洁和高效的综合策略。物理精确的结构探测技术和用户友好的数据处理，使非专家实验室能够对相关细胞环境中的大 RNA 进行轻松、全面的功能分析。我们的合作团队由 HIV 病毒学家、RNA 结构生物学家和生物信息学专家将解决以下目标：（1）使用基因组规模的 SHAPE-MaP 策略分析真实病毒颗粒内完整的 HIV-1 基因组的结构；（2）识别整个 HIV-1 基因组的空间相互作用。通过大规模、单分子、相关化学探测实验；(3) 全面定义介导包装的 HIV-1 基因组 RNA 的 RNA 相互作用组的分子内和分子间相互作用；以及 (4) 创建强大的独立于平台的软件，用于化学探测实验的全自动分析，专门测量 RNA 中的空间相互作用。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

RNA structure probing dash seq.

RNA 结构探测短划线序列。

DOI：
10.1073/pnas.1107835108
发表时间：
2011
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Weeks,KevinM
通讯作者：
Weeks,KevinM

Accurate detection of chemical modifications in RNA by mutational profiling (MaP) with ShapeMapper 2.