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

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.

项目概要 自然发生的和实验室的蛋白质修饰都是重要的研究领域，因为蛋白质是 几乎所有生物过程的核心。一方面，蛋白质翻译后修饰（PTM）是 对于有机体的正常运作至关重要，并且与许多疾病有关。这是伟大的 研究 PTM 对开发新的治疗药物具有重要意义。另一方面，继续 非规范氨基酸（ncAA）诱变的进展为操纵提供了强大的工具 以及蛋白质功能的研究。该 MIRA 应用程序旨在合并这两个方面的调查 研究领域。 MIRA 项目的第一个总体领域侧重于共翻译修饰 通过遗传密码工程获得蛋白质。长期目标是探索 ncAA 的创新策略 通过重新编程遗传密码进行诱变。我们当前和独特的重点是重新编程 具有四联体密码子 (Qcodons) 的密码子语言，尽管三联体无义密码子是主要的 用于遗传密码扩展领域的。基于我们在 tRNA 工程方面的开拓性努力，我们 通过识别和实现提出了提高Qcodon解码效率的新方向 重新编码信号。使用重新编码信号还可以显着减轻对以下问题的主要担忧： 使用基于无义抑制的非规范氨基对内源终止密码子进行不需要的通读 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 HIV-1疫苗开发的控制策略，代表了第一个新的方向 由我的小组证明。这种策略也将应用于针对其他疾病的疫苗的生产 未来的致病病毒或细菌。 MIRA 项目的第二个一般领域是调查 蛋白质酪氨酸 O-硫酸化 (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 PTS 趋化因子受体是我们长期努力研究 PTS 对受体信号传导影响的第一步 一般来说。此外，我们寻求开发针对硫酸化受体的治疗剂。这两个 创新项目有其自己的目标和意义，但统一在我们的专业知识之下 化学/合成生物学，并且彼此部分相关。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，还要使用这些工具 深入了解开发新疗法的生物医学过程。