Does YAP/TAZ signalling play a role in right-left ventricular interactions?

YAP/TAZ 信号传导在左右心室相互作用中发挥作用吗？

• 批准号: 436830268
• 负责人: Dr. Sonja Raschzok
• 金额: --
• 依托单位: The Hospital for Sick Children
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/436830268?language=en
• 关键词: Does; YAP; TAZ; signalling; play

Heart failure is the fastest rising cardiovascular disease, with a projected 25% increase over the next decade and a 25-50% one-year mortality. Treating left ventricular (LV), right ventricular (RV) and pulmonary vascular (PV) function separately has not improved outcomes. Friedberg et al. have shown in rodent models that constricting the pulmonary artery to cause RV failure leads to LV fibrosis and dysfunction. Aortic constriction causes LV failure and leads to RV fibrosis and dysfunction. Consequently, LV and RV function and failure cannot be regarded as separate entities. As the pulmonary bed lies between the left and right circulations, the lungs are an important component of RV-LV interaction. However, the molecular signalling that transmits mechanical stress of RV or LV failure into contralateral ventricle is not completely understood. The proposed project is to define the role of YAP/TAZ signalling, a powerful mechanotransducer known from pulmonary hypertension, in development of fibrosis and remodelling in RV-LV interactions. As YAP/TAZ signalling can be pharmacologically modulated, this novel and exciting approach has high potential for rapid clinical translation. A rodent animal model of RV-LV interactions as well as primary cell culture models, which mimic mechanical stress, are established in the Friedberg laboratory and will be harnessed for the aims of this proposal.

心力衰竭是发病率最快的心血管疾病，预计未来十年发病率将增加 25%，一年死亡率将增加 25-50%。单独治疗左心室 (LV)、右心室 (RV) 和肺血管 (PV) 功能并不能改善预后。弗里德伯格等人。在啮齿动物模型中表明，收缩肺动脉导致右心室衰竭会导致左心室纤维化和功能障碍。主动脉缩窄导致左心室衰竭并导致右心室纤维化和功能障碍。因此，LV 和 RV 的功能和故障不能被视为独立的实体。由于肺床位于左右循环之间，因此肺是 RV-LV 相互作用的重要组成部分。然而，将右心室或左心室衰竭的机械应力传递到对侧心室的分子信号传导尚不完全清楚。拟议的项目是确定 YAP/TAZ 信号传导的作用，YAP/TAZ 信号传导是肺动脉高压中已知的一种强大的机械转导器，在 RV-LV 相互作用中纤维化和重塑的发展中的作用。由于 YAP/TAZ 信号传导可以通过药理调节，这种新颖且令人兴奋的方法具有快速临床转化的巨大潜力。 Friedberg 实验室建立了 RV-LV 相互作用的啮齿动物模型以及模拟机械应力的原代细胞培养模型，并将用于实现该提案的目的。