Fishing out new therapeutic pathways for heart disease

Heart muscle cells (cardiomyocytes) have to integrate a lot of information to function properly. They do this by affecting activity of key players in signaling pathways: relays of cellular information that affect such processes as muscle contractions, energy metabolism and even survival of cardiomyocytes. Many drugs we use today for heart failure are targeted to a very limited number of such signaling pathways – thus limiting treatment options.

My lab uses the zebrafish embryo to examine how genes affect heart development and cardiovascular disease. Zebrafish are a common childhood pet, largely because they are hardy and easy to maintain. Its embryo is fertilized external to the mother, is optically clear, and develops rapidly, with the heartbeat starting in the first 24 hours of life.

Why the zebrafish

Science shows that mutation in zebrafish of genes associated with human heart disease leads to heart failure in zebrafish embryos – making them an excellent test tube for figuring out how signaling pathways regulate heart function. Our lab has used zebrafish to create many congenital heart disease models, and further to understand how the heart of this animal can fully regenerate as an adult.

To identify new pathways relevant to heart failure, I collaborate with Tony Gramolini, who is an expert in the field of proteomics, and principal investigator at the Ted Rogers Centre. The Gramolini lab uses sensitive mass spectrometry approaches to identify signaling pathway proteins that are highly enriched in cardiomyocytes, yet have never been studied in this context before.

New signaling pathways, new treatment targets

The levels of many of these proteins are altered in mouse models of heart failure, suggesting that they may be key players in how the disease progresses. Thanks to an Innovation Fund award from the Ted Rogers Centre, my lab is now creating zebrafish in whom these genes have been mutated.

In studying the hearts of these animals, we will identify new signaling pathways critical to heart failure. As zebrafish embryos grow in simple salt water, they can be raised in multi-well plastic plates to which robots can array large libraries of potential drugs. Mutants made in this study will be used to screen for drugs that improve heart failure, identifying new targets for the treatment of this disease.