Directed Evolution of Cell-Type Specific On-Demand Signaling Control Systems

细胞类型特定按需信号控制系统的定向进化

• 批准号: 10246098
• 负责人: Justin G. English
• 金额: $ 133.95万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246098
• 关键词: Biochemical; Biological Assay; Biological Process; Biomedical Research; Brain; Cells; Directed Molecular Evolution; Disease; Dopamine; Event; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Health; Health Promotion; Hormones; Human; Human Genome; Learning; Ligands; Methods; Modeling; Mus; Neurotransmitters; Output; Physiological; Production; Protein Engineering; Protein Family; Proteins; Research; Rewards; Signal Transduction; Signaling Protein; Smell Perception; Structure; System; Taste Perception; United States National Institutes of Health; Vision; cell type; experience; immune function; innovation; invention; pain perception; receptor; success; tool

Project Summary/Abstract This project will expand my recent inventions in directed evolution to create tools for cell-type specific photoswitchable tuning of G-protein coupled receptors. The human genome encodes >900 G-protein coupled receptors (GPCRs). Found in every cell, GPCRs contribute to every known biological process; from our sense of taste, smell, and sight to coordinating hormone, neurotransmitter, and immune functions. The past one-hundred years of biochemical research on this protein family has produced 346 structural determinations, >100,000 confirmed ligands, and a wealth of signaling assay platforms. Absent from this impressive roster are any tools for the discrete, cell-type specific tuning of endogenous receptor activity (Fig 1). Without such tools, we lack the ability to directly connect discrete GPCR signaling events to cell-type specific physiological outputs. Such tools are essential if we are to understand how GPCRs dictate human health and disease. In this NIH New Innovator proposal, I will expand my recently invented platform for mammalian directed evolution to create a production pipeline for cell-type specific, photoswitchable allosteric modulators of GPCRs. I will then develop the first of these modulators for the D1 and D2 dopamine GPCRs and use these tools to refine existing models of dopaminergic reward signaling in the murine brain. The success of this proposal will benefit every field of biomedical research, creating a pipeline to gain tunable control of not only any GPCR, but any cell signaling protein.

项目总结/文摘

项目成果

Discovery and Validation of Context-Dependent Synthetic Mammalian Promoters.

上下文相关的合成哺乳动物启动子的发现和验证。

• DOI: 10.1101/2023.05.11.539703
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Zahm,AdamM;Owens,WilliamS;Himes,SamuelR;Rondem,KathleenE;Fallon,BradenS;Gormick,AlexaN;Bloom,JoshuaS;Kosuri,Sriram;Chan,Henry;English,JustinG
• 通讯作者: English,JustinG

Advancements in G protein-coupled receptor biosensors to study GPCR-G protein coupling.

研究 GPCR-G 蛋白偶联的 G 蛋白偶联受体生物传感器的进展。

• DOI: 10.1111/bph.15962
• 发表时间: 2023
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Olsen,ReidHJ;English,JustinG
• 通讯作者: English,JustinG