Heart failure, the failing heart, heart disease, protein kinases, phosphorylation
Basic research and translational and applied research
Heart failure is a leading cause of morbidity and mortality worldwide. It occurs when the heart cannot pump the blood properly around the body. The failure to maintain an adequate blood flow (and, therefore, oxygen) to meet the requirements of the body results in symptoms such as extreme breathlessness and tiredness, with impairment of normal activities, and potentially leads to death.
The contractile cells of the adult heart (cardiomyocytes) cannot multiply. If the heart needs to work harder (e.g. because of high blood pressure) cardiomyocytes get larger to pump blood around the body more efficiently. However, they die if deprived of oxygen (e.g. during a heart attack) or exposed to toxic chemicals and, because they cannot multiply, some heart function is lost. Clearly, it would be useful to find ways of keeping cardiomyocytes alive and/or replace dead cells, whether by helping existing adult cardiomyocytes to start multiplying again or by provision of, for example, stem cells. Unfortunately, the numbers and range of new drugs directed towards treating heart failure remains limited. There is a critical need for a large expansion in the range of potential new targets so that new drugs may be developed to manage and treat heart failure.
Protein kinases are an extremely important group of molecules (enzymes) that regulate how the proteins in our body behave. For example, they can influence whether cells die, repair damaged cells or build muscle. Over 500 protein kinases are represented in human DNA, but not all are present in every cell and cardiomyocytes have a specific protein kinase complement. To perform their function, protein kinases stick to and modify other proteins, having a structure that allows them to select specific targets. This makes them ideal targets for small chemicals (i.e. drugs) that stick to individual protein kinases to prevent them from working or change what they do. This "targeted" approach is used successfully by pharmaceutical companies resulting in, for example, an increasing number of drugs for the treatment of cancer. The major problem in adapting the approach for heart failure is that the protein kinases that are most well-studied in heart were initially identified and studied in cancer or inflammation (e.g. arthritis) and we remain ignorant of the majority of the protein kinases that regulate cardiomyocytes. To unlock the full potential of protein kinases as drug targets to treat heart diseases, it is necessary to know which are present and establish how this may change during development and disease.
We aim to (i) identify the protein kinases in cardiomyocytes and the heart, and assess how this may change during development and in disease states, and (ii) establish what the kinases do in the heart and how they are regulated.
We will identify all of the protein kinases that are present in cardiomyocytes. Our preliminary work already shows that some protein kinases are present at high levels in the heart (and so can be assumed to play an important role in regulating its function) but have never been properly studied in any cell; many others have never been studied in the heart. The data will provide vital insights into why and how cardiomyocytes stop dividing and will lay a solid foundation for identifying the most suitable targets to prevent and manage heart failure. Given that many cancer drugs have been and are being developed target protein kinases, a secondary benefit of this project will be an understanding of which of these drugs is likely to affect the heart.
Knowing which protein kinases are present in cardiomyocytes and the heart will generate a large expansion in the range of potential drug targets. To ensure that the data can be exploited fully, we will publish the full dataset in an appropriate forum for access by other researchers, clinicians, industry and society as a whole). We will include our own interpretation and view of the most important candidates for drug development, and we will liaise with interested parties to develop these targets further. However, individuals will also be able to make their own assessments and select their own targets for future research.
Over the 5 years of this project, we expect to use approximately 976 rats and 246 mice.
Animals will be subjected only to terminal anaesthesia with removal of the heart immediately prior to death (i.e. non-recovery).
The contractile cells of the heart (cardiomyocytes) do not divide and there are no cell lines that are representative of these cells. It is therefore necessary to use animals to study these cells. For studies of cardiomyocyte function within the intact heart, there are no non-animal alternatives.
Cardiomyocytes are prepared under conditions that produce the greatest yield. The data from the cells are used to inform experiments with adult hearts.
When necessary, or appropriate, a professional statistician will be consulted to ensure experimental design is optimal and minimises the number of animals required, yet ensures an adequate level of precision and power, and the appropriate statistical analysis is performed.
In all cases, the minimum number of experiments will be performed to detect meaningful differences in responses with sufficient power, if they occur, at an appropriate level of statistical significance.
We will use rodents for this study. Where possible, we will use rat models which are used widely for studies of the heart.
We have worked with rats for over 20 years and have a large amount of data on protein kinases in this species on which we can base future studies.