ENDOTHELIAL GATA4 IN ATHEROSCLEROSIS PROGRESSION

动脉粥样硬化是一种动脉疾病，是导致死亡的主要原因。它的特点是脂肪沉积堆积，称为斑块。一些斑块会发展成危险的形式，可能会破裂，导致心脏病发作或中风。这一过程是由动脉弯曲或分支的复杂血流模式驱动的。这种联系的机制目前尚不清楚，可以为预防斑块破裂的新疗法提供信息。为了阐明它们，我们使用了一种无偏见的方法来识别和表征流动反应基因，并发现转录因子GATA4在驱动已知促进斑块破裂的多种过程(炎症、增殖、凋亡)方面是独一无二的。这项拟议的工作汇集了一组基础科学家和临床医生，以检验GATA4是内皮致病变化的主要调节因子以及靶向GATA4途径可以降低病变动脉破裂风险的假设。我们提出了一个雄心勃勃的研究项目，包括在小鼠身上使用条件基因敲除和分析人类冠状动脉斑块，以确定内皮GATA4在推动斑块进展为危险的易破裂形式方面的作用。重要的是，GATA4通路以前还没有在动脉粥样硬化斑块中被研究过，因此它是潜在的新药靶点方面的一个新的和有价值的资源。事实上，我们建议在GATA4途径中确定可能受药物调节的分子靶点，并可以在未来的研究中进行跟踪。拟议的研究项目具有很高的潜在影响，因为它将导致识别GATA4途径中的分子靶点，这些分子靶点可以降低斑块破裂的风险，使心脏病发作或中风的风险患者受益。

Atherosclerosis is a disease of arteries that is a leading cause of death. It is characterised by the build-up of fatty deposits called plaques. Some plaques develop into dangerous forms that can rupture leading to heart attack or stroke. This process is driven by complex blood flow patterns at bends or branches of arteries. The mechanisms of this link, which are currently unknown, could inform new therapies to prevent plaque rupture. To elucidate them, we used an unbiased approach to identify and characterise flow-responsive genes and found that the transcription factor GATA4 was unique in driving multiple processes (inflammation, proliferation, apoptosis) that are known to promote plaque rupture. The proposed work brings together a group of basic scientists and clinicians to test the hypothesis that GATA4 is a master regulator of endothelial pathogenic change and that targeting of the GATA4 pathway can reduce the risk of rupture in diseased arteries. We propose an ambitious project of research including the use of conditional knockouts in mice and analysis of human coronary artery plaques to determine the role of endothelial GATA4 in driving plaque progression towards dangerous rupture-prone forms. Importantly, the GATA4 pathway has not been studied previously in atherosclerotic plaques and it therefore represents a novel and valuable resource in terms of potential new drug targets. Indeed, we propose to identify molecular targets in the GATA4 pathway that may be amenable to pharmacological modulation and can be followed-up in future studies. The proposed research project has high potential impact because it will lead to the identification of molecular targets in the GATA4 pathway that can be targeted to reduce the risk of plaque rupture, benefiting patients at risk of heart attack or stroke.