Investigating Cellular and molecular mechanisms of cardiac remodelling

Rationale

Despite the fact that death from coronary heart disease and other cardiovascular diseases has been decreasing in many Western countries over the past few decades, these diseases are still the most common causes of death in the world.

With 54.9 million deaths occurring worldwide in 2013, 17.3 million (31%) were due to cardiovascular diseases. Of particular concern is the fact that in many developing countries and countries in transition the cardiovascular mortality is actually increasing. Coronary heart disease is the most common cardiovascular disease in Western countries. 

Following a heart attack or prolonged exposure to high blood pressure the muscle of the heart adapts. In the short term some of these adaptations prove advantageous however over the long term these changes contribute to the progression of heart failure. 

The heart 'muscle' is not homogeneous, it is made up of different cell types. One third are the actual muscle cells (the contractile cardiac myocytes) whilst the majority are non-muscle cells (fibroblasts, endothelial cells, smooth muscle cells, neuronal cells, stem cells, pericytes, inflammatory cells etc). The heart’s response to injury and the effectiveness of the repair process involves complex interactions between these many cell types and their surrounding environment.    

Plan of work

We plan to examine the complex interaction occurring in the heart 'muscle' between these very different cell types and how their interaction can be modified to bring about improvements in the way the heart remodels following an adverse cardiac event. 

To be able to dissect this complex web of interactions between different cell types and the mechanisms driving cardiac remodelling through its various stages, firstly advantageous culminating to be detrimental, it will be necessary to use transgenic mouse lines. In these transgenic animals, by selectively altering the expression of various genes and proteins involved in this remodelling process in specific cell types within the heart, we will be able to selectively disrupt the remodelling process. Improving our understanding of the underlying elements of the cardiac remodelling process and how the various cell types interact with one another and their environment will be beneficial to identify new potential therapeutic targets for future drug development. 

Animal welfare

The use of animals will only occur following careful consideration of the 3Rs. Our research strategy has been developed as far as possible using in vitro cell culture. However such simple models of cardiac cells cannot recreate the complex environment that exists in the heart in which multiple cell types communicate with one another in an organised, synchronised and dynamic environment under the influence of external factors including mechanical stress, the autonomic nervous system and various hormones. 

Non-technical summary 

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