Developing synthetic chemical biology strategies for biochemical investigations and biomedical applications

开发用于生化研究和生物医学应用的合成化学生物学策略

• 批准号: 10623497
• 负责人: Jiantao Guo
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623497
• 关键词: Amino Acids; Area; Biochemical; Biological Process; Biology; Cells; Cellular biology; Chemicals; Co-Translational Protein Processing; Code; Codon Nucleotides; Development; Disease; Engineering; Future; Generations; Genetic Code; Goals; HIV-1; Investigation; Laboratories; Language; Mammalian Cell; Mediating; Medical; Mutagenesis; Nonsense Codon; Organism; Post-Translational Protein Processing; Prevention; Process; Proteins; Quadruplet Multiple Birth; Receptor Signaling; Research; Role; Signal Transduction; Sulfate; Terminator Codon; Therapeutic Agents; Transfer RNA; Triplet Multiple Birth; Vaccines; chemokine receptor; human disease; improved; innovation; insight; novel; novel therapeutics; pathogenic bacteria; pathogenic virus; programs; protein function; receptor; synthetic biology; targeted treatment; tool; tyrosine O-sulfate; virtual; Amino Acids; Area; Biochemical; Biological Process; Biology; Cells; Cellular biology; Chemicals; Co-Translational Protein Processing; Code; Codon Nucleotides; Development; Disease; Engineering; Future; Generations; Genetic Code; Goals; HIV-1; Investigation; Laboratories; Language; Mammalian Cell; Mediating; Medical; Mutagenesis; Nonsense Codon; Organism; Post-Translational Protein Processing; Prevention; Process; Proteins; Quadruplet Multiple Birth; Receptor Signaling; Research; Role; Signal Transduction; Sulfate; Terminator Codon; Therapeutic Agents; Transfer RNA; Triplet Multiple Birth; Vaccines; chemokine receptor; human disease; improved; innovation; insight; novel; novel therapeutics; pathogenic bacteria; pathogenic virus; programs; protein function; receptor; synthetic biology; targeted treatment; tool; tyrosine O-sulfate; virtual

Project Summary Both naturally occurring and laboratory protein modifications are important fields of research since proteins are central to virtually every biological process. On one hand, protein post-translational modifications (PTMs) are essential for proper functioning of an organism and are associated with many diseases. It is of great significance to study PTMs in order to develop new therapeutic agents. On the other hand, continuing advances in noncanonical amino acid (ncAA) mutagenesis has provided powerful tools for the manipulation and study of protein function. This MIRA application seeks to merge investigations on both fronts of these research areas. The first general area of this MIRA project focuses on the co-translational modification of protein through genetic code engineering. The long-term goal is to explore innovative strategies for ncAA mutagenesis through reprogramming the genetic code. Our immediate and unique focus is on reprogramming codon language with quadruplet codons (Qcodons), although triplet nonsense codons are the predominant ones used in the field of genetic code expansion. Built on our pioneering efforts on tRNA engineering, we propose a new direction to improve Qcodon decoding efficiency through the identification and implementation of recoding signals. The use of recoding signals can also significantly mitigate a major concern over undesirable readthrough of endogenous stop codons with nonsense suppression-based noncanonical amino acid (ncAA) mutagenesis in live cell studies. We will also apply a Qcodon-dependent and ncAA-mediated control strategy to the development of HIV-1 vaccines, which represents a novel direction that was first demonstrated by my group. Such strategy will also be applied to the generation of vaccines against other pathogenic viruses or bacteria in the future. The second general area of this MIRA project is to investigate the role of protein tyrosine O-sulfation (PTS) in mammalian cell biology. Our initial efforts will focus on PTS of chemokine receptors as the first step of our long-term efforts to study the effects of PTS on receptor signaling in general. Furthermore, we seek to develop therapeutic agents targeting sulfated receptors. These two innovative projects have their own goals and significance, but are unified under our expertise in chemical/synthetic biology and are partially associated with each other. The long-term goal of my laboratory is not only to develop innovative and meaningful chemical/synthetic biology tools, but also to employ these tools to gain insights into biomedical processes for the development of novel therapeutics.

项目摘要 天然发生和实验室蛋白质修饰都是重要的研究领域，因为蛋白质是 几乎每个生物过程的核心。一方面，蛋白质翻译后修饰（PTM）为 对于有机体的正常运作至关重要，并且与许多疾病有关。它很棒 研究PTM的意义，以开发新的治疗剂。另一方面，继续 非规范氨基酸（NCAA）诱变的进步为操纵提供了强大的工具 和蛋白质功能的研究。此Mira申请旨在合并有关这些方面的调查 研究领域。这个MIRA项目的第一个一般领域侧重于共同修改 通过遗传密码工程蛋白质。长期目标是探索NCAA的创新策略 诱变通过重新编程遗传密码。我们的直接和独特的重点是重新编程 带有四倍密码子（Qcodon）的密码子语言，尽管三重态密码子是主要的 在遗传代码扩展领域中使用的。我们建立在我们在trna工程方面的开创性努力的基础上 提出一个新的方向，通过识别和实施来提高Qcodon解码效率 重新编码信号。重新编码信号的使用也可以显着减轻对 基于废话的非节制氨基的内源性终止密码子的不良读取 活细胞研究中的酸（NCAA）诱变。我们还将应用Qcodon依赖性和NCAA介导的 控制HIV-1疫苗开发的控制策略，该疫苗代表了一个新方向 由我的小组展示。这种策略也将应用于针对其他疫苗的生成 未来的致病病毒或细菌。这个MIRA项目的第二个一般领域是调查 蛋白酪氨酸O-硫酸（PTS）在哺乳动物细胞生物学中的作用。我们最初的努力将集中于 趋化因子受体是我们长期努力研究PT对受体信号传导影响的第一步 一般来说。此外，我们试图开发靶向硫化受体的治疗剂。这两个 创新项目具有自己的目标和意义，但在我们的专业知识下统一 化学/合成生物学，并部分相互关联。我实验室的长期目标是 不仅要开发创新且有意义的化学/合成生物学工具，还可以使用这些工具 为了了解新型治疗剂的生物医学过程。