Physiological relevance and signaling mechanisms of the Adhesion GPCR GPR110

Adhesion GPCR GPR110 的生理相关性和信号传导机制

• 批准号: 265992651
• 负责人: Professorin Dr. Simone Prömel
• 金额: --
• 依托单位: Institut für Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/265992651?language=en
• 关键词: Physiological; relevance; signaling; mechanisms; Adhesion

Adhesion G protein-coupled receptors (aGPCRs) fulfil essentialfunctions in developmental, immunological and neurologicalprocesses and have been shown to be highly relevant in variouspathological settings. Their exceptional architecture indicates uniquesignaling mechanisms for this receptor class. One group of aGPCRswhich is highly suitable for studies on activation and signaling due tothe conservation and common ancestry of its members is the clusterof Gpr110/Adgrf1, Gpr111/Adgrf2, Gpr115/Adgrf4 and Gpr116/Adgrf5.It has been shown that among receptors of this cluster, each aGPCRmediates distinct signals, but a tethered agonist derived from onereceptor is able to activate several members of this group. Severalstudies suggest that these receptors are associated with vitalbiological processes with GPR110 as one of the oldest membersbeing predominantly linked to metabolic functions. Despite theseindications and their interesting signaling capacities, theirphysiological functions remain vastly elusive precluding the evaluationof the impact of their signals. A mouse model knockout for Gpr110revealed that this receptor potentially plays a role in regulation ofmetabolic processes and renal function. The proposed projectfocuses on elucidation of the physiological functions of GPR110 andthe implications of its signaling mechanisms and targets two aims: 1.Analysis of the role of GPR110 in renal function and regulation ofmetabolic processes and 2. delineation of the signaling mechanismsunderlying these physiological functions. Based on own preliminarydata, these aims will be achieved using a combination of in vivo, exvivo and in vitro analyses centering around the existing knockoutmouse model, tissue culture models and the acquired knowledgeabout signaling of the receptor. The physiological relevance ofGPR110 in the kidney and a potential role in renal injury will beelucidated as well as its impact on regulation of metabolic processes.Subsequently, receptor signalling on a molecular level in the identifiedcontexts will be analyzed. Receptor activation and interaction partnerswill also be a focus of the project. The proposed research project willsubstantially contribute to the understanding of the physiologicalrelevance of the aGPCR GPR110. Moreover, findings will give furtherprofound insights into the signal transduction of aGPCRs, potentiallyaiding the evaluation of the pharmacological potential of this receptorclass.

粘附G蛋白偶联受体（adhesionG protein-coupledreceptor，aGPCRs）在发育、免疫和神经过程中发挥重要作用，并与多种病理学环境密切相关。它们特殊的结构表明了这类受体的独特信号机制。由于其成员的保守性和共同祖先性，非常适合于研究激活和信号传导的一类aGPCR是Gpr 110/Adgrf 1、Gpr 111/Adgrf 2、Gpr 115/Adgrf 4和Gpr 116/Adgrf 5的簇。一些研究表明，这些受体与重要的生物学过程有关，GPR 110是最古老的成员之一，主要与代谢功能有关。尽管有这些迹象和他们有趣的信号能力，他们的生理功能仍然非常难以捉摸，排除了评估他们的信号的影响。一个敲除Gpr 110的小鼠模型显示，该受体可能在代谢过程和肾功能的调节中发挥作用。本项目的研究重点是阐明GPR 110的生理功能及其信号传导机制，主要有两个目标：1.分析GPR 110在肾功能和代谢过程调节中的作用; 2.描绘这些生理功能的信号机制。基于自身的实验数据，将围绕现有的基因敲除小鼠模型、组织培养模型和获得的受体信号传导知识，使用体内、体外和体外分析的组合来实现这些目标。GPR 110在肾脏中的生理相关性和在肾损伤中的潜在作用将被阐明，以及它对代谢过程调节的影响。随后，将在分子水平上分析识别背景下的受体信号传导。受体激活和相互作用伙伴也将是该项目的重点。该研究项目将有助于理解aGPCR GPR 110的生理相关性。此外，这些发现将进一步深入了解aGPCR的信号转导，可能有助于评估这类受体的药理学潜力。