Understanding structural changes and altered calcium signalling in the ageing and failing heart

Elucidation of the molecular and cellular mechanisms stabilising the cardiac dyadic cleft and synchronous CA-signalling: what goes wrong in the ageing and failing heart?

Dr Ashraf Kitmitto and her collaborative team at the University of Manchester are keen to understand why elderly people are prone to heart failure and identify the changes taking place in the heart that lead to disease. Heart failure can occur when the large chambers of the heart fail to contract properly, which happens when a critical process called calcium signalling is disrupted. Within the heart key proteins interact to form ‘bridges’ that hold the membranes of heart cells together. These bridges, known as transverse tubule (TT) membranes are connected in a particular way to form tiny spaces between the heart muscle cells. The spaces, called dyadic clefts, must be a particular size and shape for calcium signalling to occur. Maintaining the integrity of these spaces, therefore, is central to effective muscle contraction. With this award the multidisciplinary team will use animal models, and organ, cellular and molecular level studies to provide a detailed view of the role of the dyadic cleft in heart failure. The team will work out the exact 3D structure of the dyadic cleft and how it is stabilized by particular membrane bound proteins including a newly identified protein, junctophilin-2 (JP-2). They will also assess how the structure of the heart’s muscle cells change during ageing and heart failure using a sheep model. The team will develop genetically modified mice that cannot produce the JP-2 protein to help them identify the role of JP-2 in heart cell membrane structure and heart function. This programme of work will reveal important information about the heart’s micro-architecture and how it changes during ageing and heart failure. It should also allow the researchers to identify potential targets for new therapies to maintain the heart’s structure, and delay heart failure.