Internet-scale discovery of RNA bioengineering rules

互联网规模发现RNA生物工程规则

• 批准号: 8668102
• 负责人: Rhiju Das
• 金额: $ 45.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-05 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668102
• 关键词: Adenine; Adoption; Algorithm Design; Algorithms; Anti-Bacterial Agents; Antiviral Therapy; Automobile Driving; Bacteria; Base Pairing; Benchmarking; Biomedical Computing; Biomedical Engineering; Chemicals; Communities; Computational algorithm; Computer Simulation; Computing Methodologies; Crowding; Data; Data Analyses; Databases; Development; Disease; Elements; Failure; Feedback; Functional RNA; Funding; Genetic; Glean; HIV; Human; In Vitro; Internet; Intuition; Knowledge; Life; Ligand Binding; Maps; Marketing; Masks; Methods; Mining; Modeling; Nanotechnology; Nucleic Acids; Nucleotides; Organism; Pattern; Performance; Play; Positioning Attribute; Publications; RNA; RNA Biochemistry; RNA Conformation; RNA Folding; RNA Sequences; RNA chemical synthesis; Research; Resolution; Retroviridae; Role; Science; Scientist; Seeds; Shapes; Social Network; Solutions; Source; Staging; Structure; Testing; Time; United States National Institutes of Health; Validation; Viral; base; cost; design; high throughput technology; insight; nanoengineering; neoplastic cell; next generation; novel; programs; repository; research study; sensor; success; tool; trend

DESCRIPTION (provided by applicant): Recent discoveries of biologically fundamental non-coding RNAs are inspiring novel antibacterial, antitumor, and antiviral therapies that might disable or manipulate the molecules involved. However, in silico folding models cannot yet confidently predict RNA conformations in vitro, slowing the development of these potentially life-saving efforts. To develop the next-generation of robust and rigorously tested RNA bioengineering rules, we are exploring an unconventional strategy: last year, we released a citizen science project enabling non-experts to develop and test folding hypotheses in internet-scale RNA design competitions that are rigorously scored through wet-lab feedback. Launched in early 2011, the 25,000-player EteRNA project already outperforms existing previous methods for designing novel RNA structures which fold properly in vitro. The critical next stage is to sustain and formalize the RNA nanoengineering insights preserved within the EteRNA community. We propose steps to consolidate the community's experimentally validated human computation into a suite of automated design algorithms (EteRNAbot) usable by the entire RNA nanoenginering community. Beyond compiling such cases, we will crowd-source the rigorous search and resolution of in silico and in vitro design failures with thousands of new experiments. Finally, we will deploy the EteRNA- 3D interface for both expert and crowd-sourced three-dimensional design, leveraging a growing database of 3D building blocks and the ROSETTA RNA folding/design algorithms. We will evaluate success in each aim via synthesis and single-nucleotide- resolution chemical mapping of novel designs through our high-throughput wet-lab pipeline. More generally, we will evaluate success by assessing the extent of utilization and citation of the automated design tools; the extent of mining and citation of the publically available RNA Mapping Database generated for the project; and the adoption of the EteRNA paradigm for Internet-scale scientific discovery in biomedical computation problems beyond nucleic acid design.

描述（由申请人提供）：生物学基础非编码 RNA 的最新发现正在启发新型抗菌、抗肿瘤和抗病毒疗法，这些疗法可能会禁用或操纵相关分子。然而，计算机折叠模型尚不能在体外自信地预测 RNA 构象，从而减缓了这些潜在的挽救生命的努力的发展。为了开发下一代强大且经过严格测试的 RNA 生物工程规则，我们正在探索一种非常规策略：去年，我们发布了一个公民科学项目，使非专家能够在互联网规模的 RNA 设计竞赛中开发和测试折叠假设，这些假设通过湿实验室反馈进行严格评分。 EteRNA 项目于 2011 年初启动，拥有 25,000 名参与者，在设计可在体外正确折叠的新型 RNA 结构方面，其性能已经优于之前的现有方法。下一阶段的关键是维持和形式化 EteRNA 社区中保存的 RNA 纳米工程见解。我们提出了将社区经过实验验证的人类计算整合为一套可供整个 RNA 纳米工程社区使用的自动化设计算法 (EteRNAbot) 的步骤。除了汇编此类案例之外，我们还将通过数千个新实验对计算机和体外设计失败进行严格的搜索和解决。最后，我们将利用不断增长的 3D 构建模块数据库和 ROSETTA RNA 折叠/设计算法，为专家和众包三维设计部署 EteRNA-3D 接口。我们将通过我们的高通量湿实验室管道对新颖设计进行合成和单核苷酸分辨率化学图谱来评估每个目标的成功与否。更一般地说，我们将通过评估自动化设计工具的利用程度和引用来评估成功；为该项目生成的公开 RNA 作图数据库的挖掘和引用程度；采用 EteRNA 范式在核酸设计之外的生物医学计算问题中进行互联网规模的科学发现。