Grant: Operating Grant

Diseases of the heart valves are among the most frequent causes of heart disease in Canada and cause significant morbidity. The most common valve disease is calcific aortic valve sclerosis. In aortic valve sclerosis, the valve leaflets thicken, stiffen, and calcify. Ultimately, these changes prevent the valve from opening and closing properly, which leads to serious heart problems. Currently, there is no effective treatment for aortic valve sclerosis except to replace the valve when the disease is advanced. The goal of this research is to better understand the biomechanical and biochemical factors that contribute to the progression of valve disease. In preliminary work, we discovered that the aortic valve contains a large population of mesenchymal stem cells, a primitive type of cell that can become various mature cell types. We showed that the stiffness of the valve tissue modulates whether these cells convert to osteoblasts that make bone or myofibroblasts that cause fibrosis when grown under disease conditions. The objective of this project is to determine the molecular mechanisms by which tissue stiffness modulates valve cell pathological differentiation. Using novel bioengineering approaches and biomaterial systems, we will determine how matrix stiffness affects signalling pathways within the cell that regulate differentiation, with particular focus on pathways that are known to play an important role in skeletal bone formation. We will then confirm these findings in normal pigs and in pigs with valve disease by measuring valve tissue stiffness and correlating it with biological markers of valve cell function. The knowledge gained by these studies will help to identify and develop novel therapeutic strategies that prevent or arrest aortic valve sclerosis, thereby reducing the impact of the disease and leading to improved health and quality of life for millions of Canadians.