Grant: Operating Grant

My laboratory studies hypertension, a disease that affects millions of Canadians (close to 30% of all adults). Characterized by sustained high blood pressure, hypertension is accompanied by heart disease leading to heart failure. Since hypertension can be lethal, but has no obvious symptoms, it is often called the silent killer. Previous discovery of factors such as the hormones angiotensin II and adrenaline which, in high levels, cause hypertension has paved the way to important anti-hypertensive drugs. These drugs include the angiotensin converting enzyme inhibitors (the well-known ACE inhibitors) and adrenaline receptor blockers (best known as alpha or beta blockers). Although these drugs are highly specific, they can fail when the disease is caused by different or by multiple pro-hypertensive hormones. Drug combinations have side-effects. In the 21st century, over 60% of all treated individuals still do not meet current treatment goals and are at risk of heart disease. These facts underscore the need for better knowledge of the mechanisms of pro-hypertensive hormones and how they cause hypertension and heart disease. Interestingly, research from my laboratory suggests that many pro-hypertensive hormones work through rather similar mechanisms. Molecular scissors (also known as proteases with names such as MMP-2, MMP-7 and ADAM-12), which are specialized in cleaving cell proteins, work downstream of pro-hypertensive hormones. Therefore, we propose to address some very important questions such as: 1) Do different pro-hypertensive hormones cause hypertension using the same proteases? 2) Do these proteases take turns to work? Do they work together? How do they regulate each other? For example does MMP-7 somehow assist MMP-2 and ADAM-12 to cause hypertension and affect the heart? 3) Which protease(s) is a good target to treat hypertension and the accompanying heart disease, when the causes of these diseases are complex or unknown?