The Cardiac Role of the Exchange Protein Directly Activated by cAMP (Epac) During Postnatal Development

During postnatal development, heart cells undergo marked changes in shape and size in order to adapt to a changing and growing organism. In addition there are changes in the way heart cells generate their electrical and contractile activity. Recent advances in research have identified a new mediator associated with the "flight or fight" conditions where the heart needs to produce more force and beat faster. Little is known about this mechanism during different stages of development and how it changes, as the heart moves towards its adult state. Interestingly, this mechanism has also been linked to protecting the heart against cardiac insults (e.g. hypoxia, a lack of oxygen flowing into the heart, or ischaemia, a stoppage in blood flow). This study aims to identify the changes that occur in the heart during development and when the heart is exposed to cardiac insults. Particular emphasis will be placed on this new mechanism. The information which we aim to gain will help to plan and develop ways to protect the developing heart, and may ultimately help tailor such strategies for use in paediatric open-heart surgery. This is important as interventions that protect the heart that are proven in adult hearts have been uncritically extended to immature hearts without taking into account these important differences as a developing heart changes.

The vulnerability of the myocardium to cardiac insults changes during postnatal development. The underlying mechanism(s) are not presently known although developmental changes in Ca2+ mobilisation could be responsible. Key regulation of cardiac Ca2+ cycling is mediated via cyclic AMP (cAMP) /protein Kinase A (PKA) signalling pathway. Recent work has also identified guanine nucleotide exchange factor directly activated by cAMP (Epac) as an additional independent and parallel cAMP signalling pathway which also appears to regulate Ca2+ cycling in cardiomyocytes. Little is known about the role of Epac in health and disease with nothing known about the role of Epac during postnatal development. The aim of this project is to test the hypothesis that "postnatal developmental changes in cAMP /Epac signalling pathways alter Ca2+ cycling under normal conditions and during cardiac insults independent of the cAMP/PKA pathway". This work will answer fundamental questions relating to developmental changes in regulation of Ca2+ cycling and will aid the rational development of strategies to protect the developing heart.

The immediate beneficiaries of this research are the basic and clinical scientists in Bristol working and interested in novel mechanisms to protect the adult and immature heart. Although this work will focus on the role of cAMP/PKA/Epac in the heart, data and information will also have impact on colleagues working on other organs (e.g. brain and kidneys) where this signalling pathway may also have protective effects. The content of the research itself has the potential to lead to development of cardioprotective strategies for use during surgery for congenital heart diseases, although as this work is concentrating on basic fundamental biology, it is likely to be some years before this potential is realised.

In a wider sense, this proposed research will significantly contribute to the development of the applicant as a clinical academic. This supports the ongoing drive for Integrated Academic Training of clinicians, and strengthens academic Anaesthesia within the region and nationally. This will assist in the dissemination of translational research knowledge and skills to other clinicians in the area.