Untersuchung eines erweiterten Interaktionsspektrums des Thyrotropin Rezeptors

这个DFG资助的项目（始于2010年）的最终目标是全面了解促甲状腺激素受体（TSHR），以及相关的分子生物学、生理学和病理生理学。因此，近年来申请人已经确定了对TSHR的重要详细见解，并发表在《内分泌评论》（2013）上。这些信息的相关性与TSHR与格雷夫斯病、甲状腺癌、格雷夫斯眼病、非自身免疫性和自身免疫性甲状腺功能亢进等致病性疾病的多种联系有关。这些经常与TSHR相关的疾病在世界范围内流行，发病率很高，因此没有针对TSHR的医疗干预措施。在这个新申请的资助期内，申请人安排了在TSHR的研究的延长，改进和最后确定。例如：单羧酸转运蛋白8被鉴定为与TSHR相互作用的蛋白。这一发现引发了一个问题，即受体的信号转导和转运体的底物易位是如何通过这种相互作用相互修改的。这两个过程的共同发生应该激发对信号传导和底物运输的全新视角。此外，TSHR的基础信号活性（不依赖于配体）非常重要，但其调控作用尚未得到全面了解。为什么TSHR表现出永久性的基础活动，它是否具有病理生理意义？为了回答这些问题，在第三供资期间计划了先进的办法。收到的新数据连同已经报告的见解将用于生物信息学支持的系统生物学分析。最后，GPCR结构的测定得到了高度的关注和成功率，特别是在过去七年中，基于适当的蛋白质制备，膜蛋白结晶和结构测定的新方法的发展（如诺贝尔化学奖，2012,Brian Kobilka, Robert Lefkowitz）。因此，本项目将利用这些知识在原子水平上揭示TSHR的膜蛋白晶体结构。综上所述，这一申请涉及在TSHR的长期研究，以继续研究这种受体。最终目的是在原子水平上缩小关于药理学性质和结构特征的知识差距。因此，这将有助于了解与TSHR激活或失活相关的病理机制，调控的分子因果关系，并改善疾病治疗的选择。

The final goal of this DFG funded project (started in 2010) concerns a comprehensive understanding of the thyrotropin receptor (TSHR), with respect to related molecular biology, physiology and pathophysiology. Accordingly to this purpose important detailed insights into the TSHR were already identified by the applicants in recent years and published in Endocrine Reviews (2013). The relevance of these information is related to the versatile links of the TSHR to pathogenic situations like Graves disease, thyroid-carcinoma, Graves' orbitopathy, non-autoimmune and autoimmune thyroid hyperfunction. These frequently TSHR associated diseases are of world-wide and high prevalence, whereby a TSHR-directed medical intervention is not available. In this newly applied period of funding the applicants scheduled the extension, refinement and finalization of studies at the TSHR. For example: the monocarboxylate-transporter 8 was identified as an interacting protein with the TSHR. This finding induces the question how signal transduction at the receptor and substrate translocation at the transporter are mutually modified by this interaction. Such a co-incidence of both processes should provoke a fundamentally new perspective on signaling and substrate transport. Furthermore, the basal signaling activity of the TSHR (ligand independent) is of high importance, but is not comprehensively understood concerning their regulative impact. Why the TSHR exhibits a permanent basal activity and is it of pathophysiological significance? To answer these questions advanced approaches are planned during a funding-period III. Received new data together with already reported insights will be used for a bioinformatic-supported systems-biology analyses. Finally the determination of GPCR structures has become high attention and success-rate especially in the last seven years based on new methods developed for appropriate protein preparation, membrane protein crystallization and structure determination (e.g. Nobel-price chemistry, 2012, Brian Kobilka, Robert Lefkowitz). Therefore, this knowledge will be used in this project for unraveling the membrane protein crystal structure of the TSHR on the atomic level. Taken together, this application concerns an extended period of studies at the TSHR to continue the investigation of this receptor. The final purpose is to close the gap of knowledge concerning pharmacological properties and structural features on the atomic level. In consequence this will help to understand pathological mechanisms related to TSHR activation or inactivation, molecular causalities of regulation and to improve options of disease treatment.