Mechanisms of spatiotemporal signaling by GPCRs
GPCR 的时空信号传导机制
基本信息
- 批准号:10722825
- 负责人:
- 金额:$ 12.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdenosineAdrenergic ReceptorAffectAgonistAnimalsAreaAscorbic AcidBehaviorBiochemicalBiochemistryBiological AssayBiologyCaliforniaCardiovascular PhysiologyCell membraneCell modelCell physiologyCellsCoupledCouplingCyclic AMPCyclic AMP-Dependent Protein KinasesDiseaseEndocrineEndocytosisEndosomesFamilyG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGTP-Binding ProteinsGoalsImaging TechniquesIn VitroIntegral Membrane ProteinKnowledgeLabelLigand BindingLigandsLinkLocationMapsMass Spectrum AnalysisMembraneMentorsMentorshipModelingMolecularMutateOutcomeOutputPathway interactionsPerceptionPeroxidasesPhasePhosphorylation SitePhysiological ProcessesPolypeptide HormonesPostdoctoral FellowProtein BiochemistryProtein translocationProteinsProteomeProteomicsReceptor ActivationReceptor SignalingRecyclingRegulationResearchResourcesSan FranciscoSensorySignal TransductionSignal Transduction PathwaySortingSystemTherapeuticTotal Internal Reflection FluorescentTrainingUniversitiesVIPR1 geneVasoactive Intestinal Peptide ReceptorsWorkbeta-arrestindesignexperienceexperimental studyfrontierinsightnovelprotein activationreceptorreceptor internalizationreceptor recyclingreconstitutionresponseskillsspatiotemporaltherapeutic targettooltraffickingtraining opportunity
项目摘要
Project Summary
G protein-coupled receptors (GPCRs) comprise the largest family of signaling receptors in animals, and as such,
they represent an important class of therapeutic targets. Following ligand binding and G protein activation at the
plasma membrane, GPCRs undergo regulated endocytosis and sorting for recycling or degradation. Traditionally,
studies of ligand-dependent GPCR signaling have focused on receptor-G protein coupling at the plasma
membrane (PM). However, it is now clear that GPCRs can continue to signal from internal membrane locations
and that the downstream responses elicited from intracellular signaling are distinct from those elicited from PM
signaling. While the biochemistry of GPCR activation has been studied in detail, the organization and regulation
of GPCR signaling in living cells remains an underexplored frontier. The proposed studies will investigate
fundamental mechanisms underpinning spatiotemporal regulation of GPCR signaling and will provide key
training to enable Dr. Blythe to become an independent leader in this emerging area of molecular and cellular
physiology. The mentored phase of this project will be carried out at the University of California, San Francisco
under the primary mentorship of Dr. Mark von Zastrow, a leader in the field of GPCR trafficking and signaling.
The long-term goals of this work are to understand (1) how the subcellular localization of GPCRs and their
associated proteins change in response to signaling and (2) how this cellular reorganization regulates their
distinct downstream responses. The first two Aims will focus on receptor trafficking and signaling, defining the
mechanisms by which unique endocytic (Aim 1) and recycling (Aim 2) pathways sculpt signaling by
endogenously expressed GPCRs in a HEK293 cell model. In carrying out these experiments, Dr. Blythe will gain
new experience in advanced imaging techniques, as well as in integral membrane protein biochemistry with the
help of Dr. Aashish Manglik (collaborator). Aim 3 frames the biology in a broader perspective by asking how the
dynamic subcellular localization of other proteins contributes to the spatiotemporal regulation of GPCR signaling.
Using a novel proximity labeling approach under the mentorship of Dr. Nevan Krogan (co-Mentor) and Dr. Ruth
Hüttenhain (collaborator), Dr. Blythe will map the changes in the proteomes of specific cellular compartments
during the activation of the same model GPCRs and explore how these changes dictate signaling. The proposed
work will enable a systems-level analysis of GPCR signaling that was not feasible with current approaches and
provide an invaluable training opportunity for Dr. Blythe in mass spectrometry-based proteomics. In summary,
this project will take advantage of the expertise of a diverse mentorship team and the world-class resources and
facilities at UCSF to tackle fundamental questions in GPCR biology.
项目摘要
G蛋白偶联受体(GPCRs)是动物中最大的信号受体家族,因此,
它们代表了一类重要的治疗靶点。在配体结合和G蛋白激活之后
质膜,GPCRs经历调节的内吞作用和分类回收或降解。传统上,
对配体依赖的GPCR信号的研究主要集中在血浆中受体-G蛋白的偶联
膜(PM)。然而,现在很明显,GPCRs可以继续从内部膜位置发出信号
细胞内信号引起的下游反应与PM引起的下游反应是不同的
发信号。虽然对gpr激活的生物化学已经进行了详细的研究,但它的组织和调控
活细胞中GPCR信号的研究仍然是一个未被探索的前沿。拟议的研究将调查
支持GPCR信号时空调控的基本机制,并将提供关键
培训使布莱斯博士成为这一新兴的分子和细胞领域的独立领导者
生理学。该项目的指导阶段将在加州大学旧金山分校进行
在马克·冯·扎斯特罗博士的主要指导下,他是GPCR贩运和信号领域的领导者。
这项工作的长期目标是了解(1)GPCRs的亚细胞定位及其
相关蛋白质对信号的响应和(2)这种细胞重组如何调节它们的
截然不同的下游响应。前两个目标将集中在受体贩运和信号传递上,定义
独特的内吞(目标1)和循环(目标2)通路塑造信号的机制
在HEK293细胞模型中内源性表达GPCRs。在进行这些实验时,布莱斯博士将获得
在先进的成像技术以及整体膜蛋白生物化学方面的新经验
Aashish Manglik博士(合作者)的帮助。Aim 3通过询问如何在更广泛的角度来构建生物学
其他蛋白质的动态亚细胞定位有助于GPCR信号的时空调控。
在内万·克罗根博士(共同导师)和露丝博士的指导下使用一种新的邻近标记方法
Hüttenhain(合作者),Blythe博士将绘制特定细胞隔间蛋白质组的变化图
在相同模型的激活期间,GPCR并探索这些变化如何指示信令。建议数
这项工作将使GPCR信令的系统级分析成为可能,而目前的方法和
为Blythe博士提供了基于质谱学的蛋白质组学方面的宝贵培训机会。总而言之,
该项目将利用多样化的指导团队的专业知识和世界级的资源和
加州大学旧金山分校的设施,以解决GPCR生物学中的基本问题。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Emily Elizabeth Blythe其他文献
Emily Elizabeth Blythe的其他文献
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{{ truncateString('Emily Elizabeth Blythe', 18)}}的其他基金
Effects of GPCR trafficking on the spatiotemporal control of signaling
GPCR 转运对信号传导时空控制的影响
- 批准号:
10330369 - 财政年份:2021
- 资助金额:
$ 12.5万 - 项目类别:
Effects of GPCR trafficking on the spatiotemporal control of signaling
GPCR 转运对信号传导时空控制的影响
- 批准号:
10560548 - 财政年份:2021
- 资助金额:
$ 12.5万 - 项目类别:
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