Cell signaling by G protein-coupled receptors

G 蛋白偶联受体的细胞信号传导

基本信息

批准号：
10623554
负责人：
Joann Trejo
金额：
$ 53.09万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623554
关键词：
Adaptor Signaling Protein Arrestins Biological Cell membrane Cell physiology Cells Development Disease Disease Progression Drug Targeting Endosomes FDA approved Family Funding Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Goals Homeostasis Human body Knowledge Laboratories Mediating Mediator Molecular Pathway interactions Pharmaceutical Preparations Process Proteins Receptor Signaling Regulation Research Signal Transduction System Technology Ubiquitin Ubiquitination druggable target improved innovation new therapeutic target p38 Mitogen Activated Protein Kinase programs receptor function response therapeutic development trafficking tumor progression ubiquitin isopeptidase vascular inflammation virtual

Adaptor Signaling Protein Arrestins Biological Cell membrane Cell physiology Cells Development Disease Disease Progression Drug Targeting Endosomes FDA approved Family Funding Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Goals Homeostasis Human body Knowledge Laboratories Mediating Mediator Molecular Pathway interactions Pharmaceutical Preparations Process Proteins Receptor Signaling Regulation Research Signal Transduction System Technology Ubiquitin Ubiquitination druggable target improved innovation new therapeutic target p38 Mitogen Activated Protein Kinase programs receptor function response therapeutic development trafficking tumor progression ubiquitin isopeptidase vascular inflammation virtual

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项目摘要

Abstract Mammalian G protein coupled receptors (GPCRs) mediate a vast array of biological responses and have been implicated in numerous diseases. GPCRs are highly druggable and the target of about one-third of all FDA approved drugs. Currently, all drugs targeting GPCRs have been developed to modulate signals transduced at the plasma membrane. However, we and others have shown that GPCRs remain active inside the cell and signal from endosomes. The orchestration of GPCR signaling from the plasma membrane and endosomes is essential for achieving proper cellular responses, dysregulation of these pathways, through either aberrant increases or decreases in signaling drives disease progression. Our laboratory has long focused on understanding the regulatory mechanisms that control GPCR signaling. In recent projects funded by MIRA, we discovered that ubiquitination of a subset of GPCRs drives p38 mitogen-activated protein kinase (MAPK) endosomal signaling and vascular inflammation. The molecular mechanisms by which key regulators and mediators of ubiquitination regulate GPCR-p38 endosomal signaling is not known and a gap in knowledge. In the next 5 years, our laboratory will focus on understanding how two key deubiquitinases regulate GPCR-stimulated p38 signaling by identifying key substrates and elucidating the mechanisms of regulation and function in vascular inflammation. We also discovered that the α-arrestin arrestin-related domain containing protein-3 (ARRDC3) is an endosomal multi-functional adaptor protein that controls GPCR signaling and trafficking via distinct mechanisms in projects funded by MIRA. Unlike classical arrestins, virtually nothing is known about the mechanisms that regulate α- arrestin activity and how α-arrestins govern mammalian GPCR function and a major gap in knowledge. In the next 5 years, we will define the molecular mechanisms that control GPCR-stimulated ARRDC3 activity and elucidate the mechanisms of regulation and function in cancer progression. We will integrate hypothesis-driven and unbiased systems approaches to interrogate the mechanisms that control ubiquitin-driven GPCR endosomal signaling and ARRDC3 activity and function utilizing innovative and cutting-edge technologies. A thorough understanding of the spatial-temporal regulatory mechanisms that control GPCR signaling is critical for improving the development of novel drugs targeting GPCRs.

抽象的哺乳动物G蛋白偶联受体（GPCR）介导了各种各样的生物反应，并且已经在许多疾病中实施。 GPCR是高度吸毒的，大约是所有FDA的三分之一的目标批准的药物。目前，所有针对GPCR的药物均已开发用于调节在以上翻译的信号质膜。但是，我们和其他人表明，GPCR在单元格内保持活跃和信号来自内体。来自质膜和内体的GPCR信号的编排是必不可少的为了实现适当的细胞反应，通过异常增加或信号传导的减少驱动疾病进展。我们的实验室长期以来一直致力于理解控制GPCR信号传导的调节机制。在Mira资助的最新项目中，我们发现 GPCR子集的泛素化驱动p38有丝分裂原激活蛋白激酶（MAPK）内体信号传导和血管炎症。关键调节器和泛素化介质的分子机制调节GPCR-P38内体信号传导尚不清楚，并且在Knowle中存在差距。在接下来的5年中，我们实验室将专注于了解两个关键的去泛素酶如何通过鉴定关键底物并阐明血管炎症中调节和功能的机制。我们还发现，含有蛋白质3（ARRDC3）的α-arrestin抑制蛋白相关域是内体多功能适配器蛋白通过项目中的不同机制控制GPCR信号和运输由Mira资助。与古典逮捕不同，几乎没有任何调节α-的机制抑制素活性以及α-arrestin如何控制哺乳动物的GPCR功能和知识的主要差距。在接下来的5年，我们将定义控制GPCR刺激的ARRDC3活性和阐明癌症进展中调节和功能的机制。我们将集成假设驱动的和无偏的系统方法来询问控制泛素驱动的GPCR内体的机制使用创新和尖端技术的信号传导和ARRDC3活性以及功能。彻底了解控制GPCR信号传导的时空调节机制对于改善至关重要针对GPCR的新型药物的开发。