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（由申请人提供）：人类基因组中只有 2% 被翻译成蛋白质，而大约 70% 被转录成 RNA。这些 RNA 中复杂的高阶结构从根本上影响关键的生物过程。例如，核糖体中的 RNA 结构是许多抗生素的靶标，HIV 和流感等 RNA 病毒基因组中的结构对于病毒复制和发病机制至关重要，与人类疾病密切相关的单核苷酸多态性中大约有一半发生在非编码区，可能反映了异常的 RNA 结构。这些结构应该在小分子药物发现工作中得到利用。 Weeks 实验室开发了一种称为 SHAPE-MaP 的化学探测策略，可以准确报告生理相关背景下的 RNA 结构。尽管独立团体将 SHAPE 描述为 RNA 结构分析的“黄金标准”，但就目前的形式而言，SHAPE-MaP 代表了一项尖端但研究级的技术。该技术基于强大的化学和“数字”大规模并行测序数据，原则上可以完全自动化。因此，Ribometrix 的长期愿景是使 SHAPE-MaP 成为一种应用于药物发现、转化研究和基础生物发现的平台技术。在这项工作中，我们将进行概念验证研究，通过两个目标解决非专家实验室采用的关键生物信息学和计算障碍：(1) 创建高效的商业级软件，将大规模并行测序数据自动解卷积为定量、经过验证的 SHAPE-MaP 反应性曲线；(2) 自动化分析流程，以快速对 RNA 结构进行建模，发现候选功能 基序以及配体和候选药物结合的定量。第 2 阶段的进展将通过可行性数据来证明，该数据显示新手研究生或技术人员级别的用户能够分析和诊断 RNA 结构探测实验，并使用自动化、容错软件识别具有可能功能重要性的 RNA 特征。在第二阶段，Ribometrix 将全面完善和集成自动化计算分析，托管在共享云计算平台上，并将为制药和学术客户及合作者开发高效的咨询服务。 SHAPE 技术的广泛应用将改变基于 RNA 的新型疗法的设计、RNA 靶标的发现以及小分子-RNA 相互作用的分析和验证。