The interactions between filamin C and small heat-shock proteins in cardiac mechanosignalling

随着每一次心跳，心脏收缩，将血液输送到全身。在每次收缩过程中，心脏的各个区域都会受到不同程度的机械压力，因此心脏细胞必须不断地感知并对这种压力做出反应。它们通过一种被称为机械信号的过程来做到这一点，在这种过程中，专门的蛋白质监测作用于细胞的机械力的变化，然后将其转化为触发体内其他重要反应的化学信号。机械信号传导是健康心脏的一项基本功能，它可能在心脏疾病中受损，例如心力衰竭，心脏泵送身体所需血液的能力减弱。心力衰竭是一个日益严重的问题。它影响着全球数百万人，其中包括英国超过92万人，在全球范围内造成的损失超过1000亿美元。主动脉瓣狭窄是一种常见的心脏瓣膜疾病，一些遗传性心脏病也涉及机械信号问题。了解机械信号如何在心脏中工作的细节，以及当它在心力衰竭和其他心脏疾病中出现故障时会发生什么，是很重要的。它可以帮助改善我们管理这些疾病的方式，并有助于开辟新的领域，探索可能的治疗方法。在这个项目中，我们的目标是了解一种特定蛋白质复合物如何执行其机械信号功能的细节。我们相信，根据我们和其他人的研究，这个复合体对心脏的机械信号传导很重要。这种复合物是由一种叫做丝蛋白C的蛋白质组成的，它对细胞结构和感知机械张力很重要，还有两种分子伴侣HSPB1和HSPB7，这两种蛋白质有助于保持其他蛋白质的形状，从而帮助细胞对机械应力做出反应。我们将确认该复合物发挥了这一作用，然后精确地探索它是如何起作用的，例如，是什么开关蛋白质活性的开启或关闭。关注这个复合体将使我们能够深入探索它是如何工作的细节。然后，我们可以应用这些原理来更普遍地理解机械信号。为了开展这项研究，我们两位专业研究人员（伯明翰大学的首席研究员PI和牛津大学的联合首席研究员Co-I）合作，将我们各自在分子工作（Co-I）和细胞和体内小鼠模型（PI）方面的优势协同结合起来。这项工作将由两名具有不同技能的博士后研究助理组成的团队进行，他们分别在一个研究小组中工作。我们的团队将得到国家和国际合作者网络的支持。这种跨学科的方法将使我们对复杂的机械信号传导有一个完整的了解，从它的构建模块的精确原子位置，到在细胞中开关它的分子事件，最后到它在动物模型中对整个心脏的影响。为了研究这个复合物，我们将进行一系列不同类型的实验，这些实验将向我们展示机械信号在分子水平、细胞和体内是如何工作的。为了研究这种复合物的结构细节以及它的成分是如何相互作用的，我们将研究从细胞中提取的蛋白质。为了研究蛋白质如何在细胞中起作用以及这对心脏功能意味着什么，我们将研究心脏细胞并使用体内模型。观察遗传性心脏病（心肌病相关的错义变异）中丝蛋白C的变化将有助于深入了解机械信号传导缺陷及其如何引发疾病。机械信号机制是我们理解心功能的基础。这项工作还将确定分子靶点，作为心力衰竭的潜在治疗方法进行进一步探索。

With every heartbeat, the heart contracts, pumping blood around the body. During each contraction, the regions of the heart experience different levels of mechanical strain, so heart cells must constantly sense and respond to this strain. They do so through a process known as mechanosignalling, where specialised proteins monitor changes in the mechanical forces acting on cells, and then convert them into chemical signals that trigger other important responses in the body. Mechanosignalling is an essential function in healthy hearts, and it may be impaired in cardiac conditions, such as heart failure, where the heart becomes less able to pump the blood needed by the body. Heart failure is a significant and growing problem. It affects millions of people globally including over 920,000 people in the UK, and costs over $100bn worldwide. Aortic stenosis, a common heart valve disorder, and some inherited heart conditions also involve problems with mechanosignalling.Understanding the details of how mechanosignalling works in the heart, and what happens when it malfunctions in heart failure and other heart conditions, is important. It can help improve how we manage these conditions and could help open up new areas to explore for possible treatments.In this project, we aim to learn the details of how one particular protein complex carries out its mechanosignalling function. We believe, based on research by ourselves and others, that this complex is important for mechanosignalling in the heart. The complex is made up of a protein called filamin C that is important for cell structure and sensing mechanical strain, along with two molecular chaperones, HSPB1 and HSPB7, - proteins that help to keep other proteins in shape - and thereby helping cells to respond to mechanical stress. We will confirm that the complex plays this role, and then explore precisely how it functions, e.g. what switches protein activity on or off. Focusing on this complex will enable us to explore the details of how it works in depth. We can then apply those principles to understanding mechanosignalling more generally. To carry out this research, we, two specialist researchers (the principal investigator, PI, at the University of Birmingham and the co-principal investigator, Co-I, at the University of Oxford) have teamed up to synergistically combine our respective strengths in molecular work (Co-I) and cellular and in vivo mouse models (PI). This work will be carried out by a team of two postdoctoral research assistants with distinct skill sets, who are embedded in one of the research groups each. Our team will be supported by a network of national and international collaborators. This interdisciplinary approach will allow us to get a complete understanding of mechanosignalling of the complex ranging from exact atomic positions of its building blocks, to molecular events switching it on and off in cells to finally its consequences on the whole heart in animal models.To study this complex, we will carry out a range of different types of experiments that will shows us how mechanosignalling works at the molecular level, in cells and in the body. To look at the details of the structure of this complex and how its components interact, we will study proteins that have been taken from cells. To look at how the proteins work in cells and what that means for heart function, we will study cardiac cells and use in vivo models. Looking at changes in filamin C occurring in inherited cardiac conditions (cardiomyopathy-associated missense variants) will give insights into defective mechanosignalling and how it triggers disease. Mechanosignalling mechanisms are fundamental to our understanding of cardiac function. This work will also identify molecular targets to be explored further as a potential treatment for heart failure.