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G(alpha)S-to-G(alpha)i switch of G protein-coupled receptor signalling in arthritis

关节炎中 G 蛋白偶联受体信号转导的 G(α)S-to-G(α)i 转换

基本信息

批准号：
355701977
负责人：
Professor Dr. Rainer H. Straub
金额：
--
依托单位：
Klinik und Poliklinik für Innere Medizin I
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/355701977?language=en
关键词：
alpha switch protein coupled receptor

项目摘要

Research in molecular cardiology and pneumology has identified an important desensitization mechanism of the Beta1/2 adrenergic receptor (also pertinent for other receptors of similar type), which is relevant in clinical medicine (heart failure, asthma). The desensitization switches canonical GalphaS signaling with increased intracellular cyclic AMP (cAMP) to Galphai signaling with low cAMP and MAP kinase activation. Phosphodiesterase inhibitors like apremilast, rolipram, or roflumilast do not work when the switch has happened. This switch was not studied in the context of immunology in rheumatic diseases, although apremilast is already in use. A similar switch seems to happen in rheumatoid arthritis (RA, our target disease), and the outcome is a proinflammatory event, which can be the important reason why apremilast does not work (shown in RA). Our preliminary results in RA clearly demonstrate signs of the switch as a proinflammatory event with increased TNF.This project will address time and proinflammatory consequence of the switch in humans already before outbreak of RA, in early RA, and late RA (time course and cell types); it will investigate the switch at different time points and in different cell types during the manifestation of collagen type II-induced arthritis (CIA) in mice; it will study the strong influence of hypoxia making use of HIF-1alpha modulators and studying the crosstalk with proteinkinase A and Erk1/2; it will scrutinize how the switch can be reverted in RA synovial cells, and whether reversion has anti-inflammatory consequences in RA synovial cells. The animal model is used in order to compare the situation in RA with CIA to define potential differences of involved pathways. These project will go beyond our preliminary work in order to demonstrate the full picture of the proinflammatory GalphaS - to - Galphai switch in RA and CIA.

分子心脏病学和呼吸病学的研究已经确定了β 1/2肾上腺素能受体的重要脱敏机制（也与类似类型的其他受体有关），这与临床医学（心力衰竭，哮喘）有关。脱敏将具有增加的细胞内环AMP（cAMP）的典型GalphaS信号传导转换为具有低cAMP和MAP激酶活化的Galphai信号传导。当转换发生时，磷酸二酯酶抑制剂如阿普斯特、咯利普兰或罗氟司特不起作用。虽然阿普斯特已经在使用，但在风湿性疾病的免疫学背景下没有研究这种转换。类似的转换似乎发生在类风湿性关节炎（RA，我们的目标疾病）中，结果是促炎事件，这可能是阿普斯特不起作用的重要原因（在RA中显示）。我们在类风湿关节炎中的初步研究结果清楚地表明，这种转换是一种促炎事件，伴随着TNF的增加。本项目将讨论在类风湿关节炎爆发前、早期类风湿关节炎和晚期类风湿关节炎中转换的时间和促炎后果（时间进程和细胞类型）;研究II型胶原诱导的关节炎（CIA）表现过程中不同时间点和不同细胞类型的转换在小鼠中;它将利用HIF-1 α调节剂研究缺氧的强烈影响，并研究与蛋白激酶A和Erk 1/2的串扰; 2它将仔细研究开关如何在RA滑膜细胞中逆转，以及逆转是否在RA滑膜细胞中具有抗炎作用。动物模型用于比较RA与CIA的情况，以确定所涉及的通路的潜在差异。这些项目将超越我们的初步工作，以展示RA和CIA中促炎性GalphaS至Galphai转换的全貌。