Significance of Piezo1 in endothelial physiology and patho-physiology

机械力对于健康人体的发育和维持是非常重要的。在心血管系统中尤其如此，因为心脏的跳动和血液在血管中的流动。例如，我们知道，排列在血管内壁的细胞（内皮细胞）对力的正确感知对于保护人们免受导致心脏病发作的冠状动脉疾病非常重要。有趣的是，人体感知机械力的过程仍然知之甚少。然而，最近发现了一种名为Piezo1的蛋白质。研究这种蛋白质可以帮助我们理解机械力是如何被感知的。这种蛋白质被发现是一种有害机械撞击的传感器。也就是说，作为外部来源的机械侮辱的探测器。我们的新数据提出了一个重要的、以前未被认识到的关于Piezo1的观点。他们认为，它也是一种更微妙的生理、内部力的传感器，这种力被称为剪应力，是血液冲向内皮细胞的结果。在本项目中，我们将在小鼠中使用新开发的Piezo1基因修饰来确定Piezo1在血管生理学和病理生理学中的意义。通过这项工作，我们将为心血管系统如何感知力提供基本的新见解。我们认为我们还将为未来开发新的心血管调节剂提供基础，以纠正或改善人体在疾病情况下感知和响应机械力的方式。这种调节剂最终可能有助于减少心血管疾病的影响，心血管疾病是世界范围内的头号杀手和致残者，也是我们社会主要财政负担的原因。

Mechanical forces are very important for the development and maintenance of a healthy human body. This is particularly true in the cardiovascular system because of the beating of the heart and the flow of blood through blood vessels. We know, for example, that correct sensing of force by cells that line the inner wall of blood vessels (the endothelial cells) is important in protecting people against coronary artery disease, which causes heart attacks. Intriguingly, the processes by which the body senses mechanical force have remained poorly understood. Recently, however, a protein called Piezo1 was discovered. Investigating this protein may help us understand how mechanical force is sensed. This protein was discovered as a sensor of noxious mechanical hitting. That is, as a detector of mechanical insult from an external source. Our new data suggest an important and previously unrecognised perspective on Piezo1. They suggest that it is also a sensor of a more subtle physiological, internal, force call shear stress, which arises as a result of the rushing of the blood against endothelial cells. In the proposed project we will use newly-developed genetic modification of Piezo1 in mice to determine the significance of Piezo1 in vascular physiology and patho-physiology. Through this work we will provide fundamental new insight into how the cardiovascular system senses force. We think we will also provide a foundation on which new cardiovascular modulators could be developed in the future to correct or improve the way the human body senses and responds to mechanical force in disease situations. Such modulators could ultimately be useful for reducing the impact of cardiovascular disease which is the number one killer and disabler worldwide and reason for major financial burden on our societies.