Physiological relevance and signaling mechanisms of the Adhesion GPCR GPR110

粘附G蛋白偶联受体（agpcr）在发育、免疫和神经过程中发挥重要作用，并已被证明在各种病理环境中高度相关。它们的特殊架构表明了这种受体类的独特信号机制。Gpr110/Adgrf1、Gpr111/Adgrf2、Gpr115/Adgrf4和Gpr116/Adgrf5是一组由于其成员的保守性和共同祖先而非常适合研究激活和信号传导的agpcr。研究表明，在这一簇的受体中，每个agpcr介导不同的信号，但从一个受体衍生的栓系激动剂能够激活该组的几个成员。一些研究表明，这些受体与重要的生物学过程有关，GPR110是最古老的成员之一，主要与代谢功能有关。尽管有这些迹象和它们有趣的信号能力，它们的生理功能仍然非常难以捉摸，妨碍了对其信号影响的评估。敲除gpr110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。本课题主要研究GPR110的生理功能及其信号机制的意义。2. GPR110在肾功能及代谢过程调控中的作用分析。描述这些生理功能背后的信号机制。基于自己的初步数据，这些目标将通过围绕现有敲除小鼠模型、组织培养模型和获得的受体信号传导知识的体内、体外和体外分析相结合来实现。gpr110在肾脏中的生理相关性及其在肾损伤中的潜在作用及其对代谢过程调节的影响将被阐明。随后，受体信号在分子水平上识别上下文将被分析。受体激活和互动伙伴也将是该项目的重点。拟议的研究项目将大大有助于了解aGPCR GPR110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潜力。

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.