The GCE4All Center: Unleashing the Potential of Genetic Code Expansion for Biomedical Research

GCE4All 中心：释放遗传密码扩展在生物医学研究中的潜力

• 批准号: 10335009
• 负责人: RYAN A MEHL
• 金额: $ 111.38万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335009
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Amino Acids; Automobile Driving; Awareness; Basic Science; Beds; Biochemical; Biological; Biological Process; Biological Response Modifier Therapy; Biomedical Research; Biomedical Technology; Biophysics; Cancer Etiology; Cardiovascular Diseases; Cations; Cell Line; Cells; Cellular Structures; Chemicals; Collaborations; Communities; Community Networks; Development; Diabetes Mellitus; Diagnostic; Diagnostic tests; Disease; Education; Educational workshop; Engineering; Ensure; Escherichia coli; Evolution; Foundations; Funding; Genetic Code; Geography; Goals; Heart Diseases; Inflammation; International; Knowledge; Label; Leadership; Life; Ligation; Longevity; Malignant Neoplasms; Mammalian Cell; Methods; Mission; Molecular; Molecular Structure; Nerve Degeneration; Oregon; Pain; Parkinson Disease; Pathogenesis; Pharmaceutical Preparations; Physiological; Post-Translational Protein Processing; Process; Production; Property; Protein Dynamics; Proteins; Protocols documentation; Reaction; Reagent; Regulation; Reproducibility; Research; Research Personnel; Site; Specialist; Speed; System; Technology; Testing; Tetanus Helper Peptide; Therapeutic; Training; Training Activity; Training Support; Translations; United States National Institutes of Health; Universities; Work; analog; base; cellular engineering; cohesion; community engagement; design; experience; functional group; improved; innovation; interest; knowledgebase; peer; peer support; programs; protein function; protein structure function; public repository; repository; symposium; synergism; technology development; tool; web site; wiki

The proposed GCE4All Biomedical Technology Development and Dissemination Center at Oregon State University (OSU) will optimize, develop, and broadly disseminate Genetic Code Expansion (GCE) technology – the engineering of cellular translation to express proteins containing non-canonical amino acids (ncAAs). GCE provides unprecedented ways to probe and manipulate macromolecular structure and function, analyze protein malfunctions in disease, engineer bioanalytical tools, and create new precision biotherapeutics. GCE's feasibility is well-established, but it remains difficult for researchers to access and implement, and thus remains little-used – an ideal target for BTDD support. During its envisioned lifespan of ≤15 years, the Center's mission will be to optimize and extend existing GCE technologies to enable facile use by non-specialists, and to broadly disseminate them via widespread education, effective training, and by providing sustainable access to optimized technologies via established repositories – enabling powerful GCE approaches to become standard, widely-used tools of biomedical researchers. Advantageous for creating the proposed Center is our experience and leadership in the groundbreaking predecessor OSU Unnatural Protein (UP) Facility (2012-21), which at a much smaller level developed and disseminated GCE methods and trained researchers. GCE4All Center leaders are thus well- equipped to accomplish the Center mission via its 2 Technology Development Projects (TDPs), 10 initial Driving Biomedical Projects (DBPs), and Community Engagement (CE). The synergistic TDPs will optimize and extend GCE methods for 1) bioorthogonal ligation applications using GCE-produced proteins, including low- background labeling and tracking in mammalian cells, and 2) producing ncAA-proteins that contain biochemical probes and/or native or analog post-translational modifications (PTMs) – ubiquitous but little-understood regulators of protein functions. To ensure broad relevance, targeted technology advances will overcome barriers faced by geographically-diverse, NIH-funded DBPs that will serve as stringent testbeds for the work. To achieve its “GCE for All”goal, Center optimizations will bridge 4 common technological barriers that deter researchers from adopting GCE. These 4 GCE Bridges include: effective tools for 1) incorporating ncAAs of choice; for efficiently producing impurity-free GCE proteins in 2) E. coli and 3) mammalian cells; and 4) creation of stable mammalian cell lines and reliable protocols for reproducible studies in cells. The CE core will provide diverse training activities including hands-on workshops already proven effective by our UP Facility. Via the Center website, CE will disseminate GCE methods, online training, and host a Wiki GCE-knowledgebase and a GCE4All community networking bulletin board enabling peer-to-peer support in the GCE user community. The CE core will also organize biennial International GCE Conferences and ensure all optimized reagents are publicly available from repositories. The GCE4All Center will achieve these ambitious goals in Years 1-5, toward its ultimate goal of transforming GCE from a boutique method to a standard part of the molecular biologist's toolkit.

拟议中的俄勒冈州GCE 4 All生物医学技术开发和传播中心 大学（OSU）将优化，开发和广泛传播遗传密码扩展（GCE）技术- 细胞翻译工程以表达含有非典型氨基酸（ncAA）的蛋白质。GCE 提供了前所未有的方法来探测和操纵大分子结构和功能，分析蛋白质， 疾病故障，工程生物分析工具，并创造新的精确生物治疗。GCE的可行性 已经建立，但研究人员仍然难以访问和实施，因此很少使用 - 是支持BTDD的理想目标。在其≤15年的预期寿命内，该中心的使命将是 优化和扩展现有的GCE技术，使非专业人员能够轻松使用，并广泛传播 通过广泛的教育，有效的培训，并通过提供可持续的优化技术， 通过已建立的知识库-使强大的GCE方法成为标准的、广泛使用的工具， 生物医学研究人员。建立拟议的中心是因为我们在这方面的经验和领导力。 开创性的前身俄勒冈州立大学非天然蛋白质（UP）设施（2012-21），它在一个小得多的水平 制定和传播全球竞争力方法，培训研究人员。GCE 4所有中心的领导人都很好- 装备完成中心使命通过其2个技术开发项目（TDPs），10个初始驱动 生物医学项目（DBP）和社区参与（CE）。协同的TDPs将优化和扩展 GCE方法用于1）使用GCE产生的蛋白质的生物正交连接应用，包括低- 哺乳动物细胞中的背景标记和跟踪，以及2）产生含有生物化学物质的ncAA-蛋白质， 探针和/或天然或类似的翻译后修饰（PTM）-普遍存在，但了解甚少 调节蛋白质功能。为了确保广泛的相关性，有针对性的技术进步将克服障碍 面对地理上多样化的，NIH资助的DBPs，将作为严格的试验台的工作。实现 其“全民GCE”目标，中心优化将弥合4个常见的技术障碍，阻止研究人员 通过GCE。这4个GCE桥梁包括：有效的工具，1）纳入选择的ncAA; 在2）E.大肠杆菌和3）哺乳动物细胞;和4）产生稳定的 哺乳动物细胞系和可靠的细胞中可重复研究的协议。CE核心将提供多种 培训活动，包括实践研讨会，已经被我们的UP设施证明是有效的。经由中心 网站，CE将传播GCE方法，在线培训，并主办一个Wiki GCE知识库和一个GCE 4All 社区联网公告板，使GCE用户社区能够提供对等支持。CE核心 我还将组织两年一次的国际GCE会议，并确保所有优化的试剂都公开 从repositories。GCE 4All中心将在第1-5年实现这些雄心勃勃的目标， 最终目标是将GCE从精品方法转变为分子生物学家工具包的标准部分。