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

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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.