Forsøksdyr: PRODH replacement in heart failure


Godkjenningsdato 16.04.2018

Cardiovascular diseases are by far the main cause of death in humans, and current pharmacological therapies are not able to revert the damage cause by acute cardiac events such as myocardial infarction, which leads to severe heart failure. The lack of effective therapies lead to a huge burden in public health and patient's quality of life. This challenge motivated us to search for new therapeutic options to treat heart failure, which are the background for this project.

We have used physical activity as a platform, to discover the genes activated by exercise in the failing heart. In the past three years, we have focused our efforts to discover these genes and after extensive experiments in vitro and in cardiac cell models, we have sufficient data to propose that a gene called Proline Dehydrogenase (PRODH) is disrupted in heart failure and is rescued by exercise. By manipulating PRODH in cardiac cells in culture, we were able to describe a series of benefits that are desirable for a failing heart, such as improved bioenergetics (mitochondrial function) and redox balance. Based on these data, here we apply to move on to the next step of the project, which is to manipulate PRODH in vivo, using adult rats. The main tasks involving animals are:

1- Use adeno-associated virus (AAV) to manipulate PRODH in heart failure rats. We have tested the AAVs protocol in this laboratory before (FOTS 5412), and it did not show any measurable side-effect.

2- Measure the rats' cardiac function using ultrasound (rats under anaesthesia)

3- Measure the rats' running capacity using treadmill running tests.

4- Sacrifice the animals and collect their hearts for further analyses.