Endosomes as a multifunctional hub to control GPCR function

内体作为控制 GPCR 功能的多功能枢纽

• 批准号: 10201677
• 负责人: Braden Lobingier
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10201677
• 关键词: Address; Area; Automobile Driving; Biological; Biology; Cell surface; Cells; Chemicals; Clinic; Consensus; Drug Targeting; Endosomes; Event; Family; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genetic Engineering; Genomics; Goals; Health; Human; Kinetics; Knowledge; Mediating; Membrane; Modeling; Molecular; Pathway interactions; Pharmaceutical Preparations; Population; Process; Proteins; Proteomics; Signal Transduction; Signaling Molecule; Signaling Protein; Sorting - Cell Movement; Testing; Work; beta-2 Adrenergic Receptors; drug development; improved; novel therapeutics; receptor; receptor function; response; targeted treatment; trafficking

Project Summary/Abstract GPCRs are the largest family of membrane bound signaling molecules and, collectively, the target of many drugs currently used in the clinic. Classically, GPCRs were thought to be active at the cell surface and inactive while undergoing molecular sorting and trafficking events within the cell. Recent work has overturned this model. GPCRs are not quiescent inside of cells. Instead, it is now known that GPCRs can activate G protein signaling from many intracellular compartments including the endosome, and this intracellular signaling changes drug response. While efforts are already underway to harness endosomal GPCR signaling as a drug target, much is unknown about GPCR sorting at endosomes and how these trafficking processes control endosomal GPCR signaling. The goal of this proposal is to address the knowledge gap surrounding GPCR sorting at endosomes, and to determine how these pathways control endosomal signaling. In Project 1 we test the hypothesis that endosomal sorting functions as a kinetic timer to control GPCR signaling at endosomes. We examine a prototypical GPCR, the beta 2 adrenergic receptor, and the use a combination of genetic engineering and proteomics to determine how sorting controls endosomal signaling. In Project 2 we focus on two different GPCRs which signal at endosomes but lack any of the consensus endosomal sorting motifs. We use a combination of chemical biology, genomics, and proteomics to identify the proteins and pathways which mediate endosomal sorting of these receptors. Our studies seek to reveal fundamental lessons about conserved cell biological pathways while driving forward a new area for future GPCR drug development.

项目概要/摘要 GPCR 是最大的膜结合信号分子家族，并且是许多药物的靶标 目前临床上使用的药物。传统上，GPCR 被认为在细胞表面活跃，而在细胞表面不活跃。 同时在细胞内进行分子分选和运输活动。最近的工作推翻了这一点 模型。 GPCR 在细胞内并不静止。相反，现在已知 GPCR 可以激活 G 蛋白 来自包括内体在内的许多细胞内区室的信号传导，以及这种细胞内信号传导 改变药物反应。虽然人们已经在努力利用内体 GPCR 信号作为药物 对于内体上的 GPCR 分选以及这些运输过程如何控制还有很多未知 内体 GPCR 信号传导。该提案的目标是解决 GPCR 方面的知识差距 在内体上进行分选，并确定这些途径如何控制内体信号传导。在项目1中我们测试 假设内体分选作为动态计时器来控制内体的 GPCR 信号传导。 我们研究了原型 GPCR、β2 肾上腺素受体，并结合使用遗传基因 工程和蛋白质组学以确定分选如何控制内体信号传导。在项目 2 中，我们重点关注 两种不同的 GPCR 在内体上发出信号，但缺乏任何共有的内体分选基序。我们 结合化学生物学、基因组学和蛋白质组学来识别蛋白质和途径 介导这些受体的内体分选。我们的研究旨在揭示有关的基本教训 保守的细胞生物学途径，同时推动未来 GPCR 药物开发的新领域。