Structure of the HIV-1 Genome

HIV-1 基因组的结构

• 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
• 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

 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（通过应用程序提供）：该项目着重于在生物学相关环境中RNA分子的三维结构的表征，将生物医学科学中重要的重要问题联系起来。首先，人类免疫缺陷病毒（HIV）目前每年感染了3500万人，每年大约300万个新感染。该病毒蛋白质成分的研究导致了多种有效药物的发展，但需要其他有效的抗逆转录病毒剂。原则上，RNA基因组本身是一个引人注目的药物靶标。我们已经鉴定出的HIV -1基因组RNA中配置的功能基序 - 我们将以本提案的一部分来表征的元素，作为抗逆转录病毒药物开发的新靶标和途径具有显着的希望。其次，在HIV-1 RNA基因组的高阶结构中编码的非常重要的信息密度代表了遗传密码的关键组成部分，我们目前了解到这一点。该研究计划将增强我们对控制RNA介导的基因调控原理的理解。它还将提高我们对RNA病毒基因组的组织和压实的理解，并将阐明适用于包括LNCRNA，核体和其他调节元素在内的纯粹有组织的RNA的原则。第三，由我们的实验室开创的形状探测策略会产生定量但高度特定的核丁基分辨率信息，因此，我们现在专注于开发多种，替代性的互补策略，这些策略在RNA中专门通过空间和高阶相互作用进行了特定检测。最后，在整个项目中，我们将创建综合策略，通过非预报实验室在相关的蜂窝情况下，通过用户友好的数据处理融合了多个，完整的，实验性的简洁和物理准确的结构探测技术，以使大型RNA在相关的蜂窝情况下进行较大的功能分析。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的：（1）使用基因组规模的形状映射策略分析正宗病毒元体内完整的HIV-1基因组的结构； （2）通过大规模，单分子相关的化学探测实验来确定整个HIV-1基因组之间通过空间相互作用； （3）全面定义了介导包装HIV-1基因组RNA的RNA相互作用组的分子间和分子间相互作用； （4）创建可靠的平台独立软件，以完全自动化化学探测实验的分析，这些软件专门测量了RNA中的空间相互作用。

项目成果

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

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

• DOI: 10.1261/rna.061945.117
• 发表时间: 2018-03
• 期刊: RNA (New York, N.Y.)
• 作者: Busan S;Weeks KM
• 通讯作者: Weeks KM