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Controlling Cardiomyocyte Dyadic Structure

Periodic Reporting for period 3 - CARDYADS (Controlling Cardiomyocyte Dyadic Structure)

Reporting period: 2018-07-01 to 2019-12-31

Contraction and relaxation of the heart are dependent on the function of individual muscle cells. Within these cells are small structures called dyads, which are junctions between two cellular membranes. During the heartbeat, release of calcium occurs at these dyads, which triggers contraction, and relaxation occurs as calcium is removed. Existing data indicate that dyads are broken down during diseases such as heart failure, which reduces the power of the heartbeat. In order to treat these patients, we aim to precisely understand how dyads work and what regulates their structure. What are the specific consequences of changing dyadic structure, and can we repair dyads in disease? The present project aims to answer these questions.
Since the beginning of the project in mid-2015, our group has made several interesting discoveries. These can be divided into 3 parts, which describe our 3 areas of scientific focus:

1. Examining dyadic structure in unprecedented detail
We have begun employing state-of-the-art technologies to understand the 3D structure of dyads. These techniques include super-resolution imaging and electron microscopy, both of which are able to separate objects which are as close together as a few nanometers (billionths of a meter). These studies have illustrated how the membranes are placed within dyads, and the precise 3D locations of different proteins that transport calcium. We have observed how these membranes and proteins are assembled as the heart develops, and how many of these constituent parts of dyads are degraded during heart failure.

2. Determining the precise consequences of changing dyadic structure
It is critical that we link how the structure of dyads affects their function, and thus the function of the entire heart. Therefore, our work to date has involved measurements of calcium in the cell. We are able to measure calcium being transported by individual dyads, and with the help of mathematical models, understand how the structure of the dyad affects calcium regulation. Our data show that breakdown of dyads during disease has serious detrimental consequences for how calcium is transported. This results in impaired contraction and relaxation of the cell. Thus, during heart failure, the overall dysfunction of the whole heart can be traced in part to tiny changes in dyadic structure and function within the heart's muscle cells.

3. Finding signals that control dyadic structure
Little has been known of the signals that regulate how dyads are put together and kept intact. Our studies in this project have shown that high physical stress placed on the walls of the heart is a key trigger for breaking dyads down. This has important implications for heart failure, as the hearts of these patients are under significant stress. Our data show that proteins which are necessary for anchoring dyads in place are lost during these high stress conditions, causing dyads to degrade. We have also identified other signals that act to build new dyads. While still testing these new concepts, we hope that by using this knowledge we can build and/or maintain dyads to strengthen the heartbeat in heart failure patients.
Heart failure has an enormous socio-economic burden and current treatments are inadequate. Instead of simply treating disease symptoms, we must strive to identify the key underlying events that cause heart failure to progress, and find ways to reverse or prevent them. The results of our study show that changes in cell structures called dyads are an important cause of this disease. Our progress thus far in the project has yielded unprecedented insight into the precise structure of dyads, the consequences of changing these structures, and the signals which are important for forming and maintaining them. We have specifically identified new pathways which lead to loss of dyads during heart failure. In the coming phase of the project, we will test new approaches to block these pathways, and stimulate other pathways which we believe to be helpful. While initial experiments will be conducted in cells, we aim to move towards human therapies in the near future.