SHAPE RNA Bioinformatics for Therapeutics and Translational Research

用于治疗和转化研究的 SHAPE RNA 生物信息学

• 批准号: 9046992
• 负责人: Kevin M Weeks
• 金额: $ 22.46万
• 依托单位: RIBOMETRIX, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-02 至 2018-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9046992
• 关键词: Adoption; Affect; Affinity; Antibiotics; Antisense Oligonucleotides; Area; Binding; Bioinformatics; Biological; Biological Markers; Biological Process; Biology; Cell physiology; Cellular Stress; Chemicals; Chemistry; Cloud Computing; Complex; Computational Biology; Computer Analysis; Computer software; Consult; Data; Diagnosis; Disease; Formulation; Genome; Gold; Government; HIV; Higher Order Chromatin Structure; Human Genome; Influenza; Laboratories; Ligands; Massive Parallel Sequencing; Medical; Messenger RNA; Methods; Modeling; Molecular Biology; Nucleic Acids; Nucleotides; Pharmaceutical Preparations; Pharmaceutical Services; Pharmacologic Substance; Phase; Process; Proteins; RNA; RNA Viruses; RNA analysis; Reading; Reporting; Research; Research Personnel; Resolution; Ribosomes; Role; Science; Services; Signal Transduction; Single Nucleotide Polymorphism; Site; Small Business Technology Transfer Research; Structure; System; Technology; Testing; Therapeutic; Transcript; Translating; Translational Research; Untranslated RNA; Validation; Viral Pathogenesis; Virus Replication; Vision; Work; base; design; digital; drug candidate; drug discovery; graduate student; high throughput technology; human disease; interest; laboratory development; novel; prototype; public health relevance; research study; small molecule; therapeutic development; therapeutic target; user-friendly

 DESCRIPTION (provided by applicant): Only 2% of the human genome is translated into proteins, whereas roughly 70% is transcribed into RNA. Complex higher-order structures in these RNAs fundamentally affect critical biological processes. As examples, RNA structures in the ribosome are the targets of many antibiotics, structures in the genomes of RNA viruses like HIV and influenza are essential for viral replication and pathogenesis, and roughly half of the single nucleotide polymorphisms that are most strongly associated with human diseases occur in non-coding regions and likely reflect abnormal RNA structures. These structures should be exploited in small-molecule drug discovery efforts. The Weeks laboratory has developed a chemical probing strategy, called SHAPE-MaP that accurately reports on RNA structure in physiologically relevant contexts. Although independent groups describe SHAPE as the "gold standard" of RNA structure analysis, in its current form, SHAPE-MaP represents a cutting-edge but research- grade technology. This technology is based on robust chemistry and "digital" massively parallel sequencing data and, in principle, could be fully automated. The long-term vision of Ribometrix is thus to make SHAPE-MaP a platform technology with applications in drug discovery, translational research, and basic biological discovery. In this work, we will conduct proof-of-concept studies to solve critical bioinformatic and computational impediments to adoption by non-expert laboratories via two Aims: (1) Create efficient commercial-grade software for automated deconvolution of massively parallel sequencing data into quantitative, validated SHAPE-MaP reactivity profiles and (2) Automate analysis pipelines to allow rapid modeling of RNA structures, discovery of candidate functional motifs, and quantification of ligand and drug candidate binding. Progress to Phase 2 will be justified by feasibility data showing that novice graduate student or technician-level users are able to analyze and diagnose RNA structure probing experiments and identify RNA features with likely functional importance using automated, error-tolerant software. In Phase 2, Ribometrix will fully refine and integrate automated computational analysis to be hosted on a shared cloud computing platform and will develop efficient consulting services for pharmaceutical and academic customers and collaborators. Widespread access to SHAPE technology will transform design of novel RNA-based therapeutics, discovery of RNA targets, and analysis and validation of small molecule-RNA interactions.

 描述（由适用提供）：只有2％的人类基因组被翻译成蛋白质，而大约70％的人被转化为RNA。这些RNA中的复杂高阶结构从根本上影响关键的生物学过程。作为示例，核糖体中的RNA结构是许多抗生素的靶标，HIV和HIV和影响力等RNA病毒基因组中的结构对于病毒复制和发病机理至关重要，而单一核丁基多态性大约有一半，这些多态性与人类疾病最有很强的与人类疾病有关，并可能在非编码区域中发生反映Abnormal rna Morder rna Morder rna Morder rna Morder rna Morder rna mords rnal mords rnal mords rnal mords rnal mords rnal mords rnamans rnal mords rnal mords rnal mords rnamors rnal mords rnamors rnamors rnal mords rnal mords。这些结构应在小分子的药物发现工作中进行探讨。几周实验室已经制定了一种化学探测策略，称为形状图，该策略在物理相关的环境下准确地报告了RNA结构。尽管独立组将形状描述为RNA结构分析的“黄金标准”，但以其当前形式形式，Shape-Map代表了一种尖端但研究级的技术。该技术基于强大的化学和“数字”大规模平行的测序数据，并且原则上可以完全自动化。因此，Ribometrix的长期视野是将Shape-Map成为平台技术，并在药物发现，翻译研究和基本生物学发现中应用。在这项工作中，我们将进行概念验证研究，以解决非专家实验室采用的关键生物信息学和计算障碍，通过两个目的：（1）创建有效的商业级软件，以将大量平行测序数据自动化为定量的，验证的形状模型反应性和（2）自动化的构建piperna的构建典范的自动化卷积，以实现定量的验证，并允许快速构建统治模型。基序，配体和候选药物的结合数量。可行性数据将证明对第2阶段的进展是合理的，表明新型研究生或技术人员级用户能够分析和诊断RNA结构探测实验，并使用自动化，容易耐受的软件识别具有功能重要性的RNA特征。在第2阶段，RiboMetrix将完全完善并整合自动化计算分析以在共享云计算平台上托管，并将为药品和学术客户和合作者开发有效的咨询服务。对Shape Technology的广泛访问将改变基于RNA的新疗法的设计，RNA靶标的发现以及对小分子RNA相互作用的分析和验证。