Untersuchung eines erweiterten Interaktionsspektrums des Thyrotropin Rezeptors

促甲状腺素受体的扩展相互作用谱的研究

• 批准号: 162103536
• 负责人: Professorin Dr. Heike Biebermann
• 金额: --
• 依托单位: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/162103536?language=en
• 关键词: Untersuchung; eines; erweiterten; Interaktionsspektrums; des

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.

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）的相关分子生物学，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《内分泌综述》（2013）中。这些信息的相关性与TSHR与致病情况如Graves病、甲状腺癌、Graves眼眶病、非自身免疫性和自身免疫性甲状腺功能亢进的多功能联系有关。这些常见的TSHR相关疾病在世界范围内普遍存在，且患病率很高，因此无法获得TSHR指导的医疗干预。在这一新申请的资助期内，申请者计划延长、完善和完成TSHR的研究。例如：单羧酸转运蛋白8被鉴定为与TSHR相互作用的蛋白质。这一发现引起的问题，如何在受体和底物转运转运的信号转导相互修改这种相互作用。这两个过程的巧合应该引起一个从根本上新的角度对信号和底物运输。此外，TSHR的基础信号传导活性（配体非依赖性）是非常重要的，但关于它们的调节影响还没有被全面理解。为什么TSHR表现出永久性的基础活动，它是否具有病理生理学意义？为了回答这些问题，计划在第三个供资期采用先进的方法。收到的新数据以及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结构的测定已成为高度关注和成功率，特别是在过去七年中，基于为适当的蛋白质制备、膜蛋白结晶和结构测定开发的新方法（例如，Nobel-price chemistry，2012年，Brian Kobilka，Robert Lefkowitz）。因此，这些知识将用于本项目，在原子水平上解开TSHR的膜蛋白晶体结构。总之，本申请涉及TSHR的延长研究期，以继续研究该受体。最终目的是缩小有关药理学性质和原子水平上结构特征的知识的差距。因此，这将有助于了解与TSHR激活或失活相关的病理机制，调节的分子因果关系，并改善疾病治疗的选择。

项目成果

Constitutive activities in the thyrotropin receptor: regulation and significance.

• DOI: 10.1016/b978-0-12-417197-8.00003-1
• 发表时间: 2014-01-01
• 期刊: Advances in pharmacology (San Diego, Calif.)
• 作者: Kleinau, Gunnar;Biebermann, Heike
• 通讯作者: Biebermann, Heike

Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation

• DOI: 10.1186/1756-6614-4-s1-s8
• 发表时间: 2011-01-01
• 期刊: THYROID RESEARCH
• 影响因子: 2.2
• 作者: Biebermann, Heike;Winkler, Franziska;Kleinau, Gunnar
• 通讯作者: Kleinau, Gunnar

A new phenotype of nongoitrous and nonautoimmune hyperthyroidism caused by a heterozygous thyrotropin receptor mutation in transmembrane helix 6.

跨膜螺旋6杂合促甲状腺激素受体突变引起的非甲状腺肿和非自身免疫性甲状腺功能亢进症的新表型

• DOI: 10.1210/jc.2010-0112
• 发表时间: 2010
• 期刊: The Journal of clinical endocrinology and metabolism
• 作者: Winkler F;Kleinau G;Tarnow P;Rediger A;Grohmann L;Gaetjens I;Krause G;L'Allemand D;Grüters A;Krude H;Biebermann H
• 通讯作者: Biebermann H

Genetic defects, thyroid growth and malfunctions of the TSHR in pediatric patients.

儿科患者的遗传缺陷、甲状腺生长和 TSHR 功能障碍

• DOI: 10.2741/3654
• 发表时间: 2010
• 期刊: Frontiers in bioscience
• 作者: Biebermann H;Winkler F;Kleinau G
• 通讯作者: Kleinau G

Principles and Determinants of G-Protein Coupling by the Rhodopsin-Like Thyrotropin Receptor

• DOI: 10.1371/journal.pone.0009745
• 发表时间: 2010-03-18
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Kleinau, Gunnar;Jaeschke, Holger;Krause, Gerd
• 通讯作者: Krause, Gerd