Impact of GATA transcription factors on mechanical load dependent myocardial fibroblast activation, migration and protective paracrine signalling in heart disease

GATA转录因子对心脏病中机械负荷依赖性心肌成纤维细胞活化、迁移和保护性旁分泌信号的影响

• 批准号: 250583393
• 负责人: Professor Dr. Jörg Heineke
• 金额: --
• 依托单位: European Center for Angioscience (ECAS)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/250583393?language=en
• 关键词: Impact; GATA; transcription; factors; mechanical

Cardiac fibroblasts turn into myofibroblasts during cardiac overload and act as first responders to limit tissue injury by secreting extracellular matrix and growth factors. On the other hand they contribute to the development of pathological fibrosis and thereby trigger cardiac dysfunction. We hypothesize that GATA4 and GATA6 act as stress sensors and coordinate the mechanoresponse in cardiac myofibroblasts during chronic cardiac overload as it occurs for example in patients with chronic arterial hypertension or aortic valve stenosis. In order to examine our hypothesis, we are generating fibroblast specific GATA4, GATA6 and GATA4/GATA6 compound knock-out mice. We will investigate the impact of these fibroblast GATA factors on myofibroblasts function and gene-expression as well as on cardiac remodelling and function during pressure overload due to experimental transverse aortic constriction. In addition, we will analyze the signalling mechanisms leading to fibroblast GATA activation as well as the mechanisms of GATA dependent transcription in these cells.

心脏成纤维细胞在心脏超负荷期间转变为肌成纤维细胞，并作为第一反应者通过分泌细胞外基质和生长因子来限制组织损伤。另一方面，它们促进病理性纤维化的发展，从而引发心脏功能障碍。我们假设 GATA4 和 GATA6 充当压力传感器，并在慢性心脏超负荷期间协调心肌成纤维细胞的机械反应，例如在患有慢性动脉高血压或主动脉瓣狭窄的患者中发生的情况。为了检验我们的假设，我们正在培育成纤维细胞特异性 GATA4、GATA6 和 GATA4/GATA6 复合敲除小鼠。我们将研究这些成纤维细胞 GATA 因子对肌成纤维细胞功能和基因表达的影响，以及对实验性横主动脉缩窄造成的压力超负荷期间心脏重塑和功能的影响。此外，我们将分析导致成纤维细胞GATA激活的信号机制以及这些细胞中GATA依赖性转录的机制。