Grant: Foundation Grant

Cardiac; Clinical Trials; Enzyme Inhibitor Pharmacology; Ischemic/Inflammatory Heart Disease; Matrix Metalloproteinases; Mitochondria; Mitochondria-Associated Membrane; Nuclei; Protease Substrates; Protein Structure; Reactive Oxygen-Nitrogen Species; Skeletal And Smooth Muscles

<html> <body> <p> <strong>MATRIX METALLOPROTEINASES IN HEART DISEASE: FROM BENCH TO BEDSIDE</strong> <br> In many heart diseases, impaired contractile function of the heart is triggered by oxidative stress. This involves the activation of matrix metalloproteinases (MMPs) in cardiac muscle. I discovered that MMPs have intracellular actions that cause contractile dysfunction in both ischemic heart disease and heart failure. Intracellular MMP&#x2011;2 (intMMP&#x2011;2) is a unique therapeutic target compared to the extracellular MMPs. Drugs that inhibit intMMP&#x2011;2 will be effective in treating heart disease with fewer side effects.<br> <br> <strong>Overarching Research Program Vision</strong> <br> I will elucidate the pathological and physiological roles of intMMP&#x2011;2 and translate this knowledge into effective new therapies for ischemic heart disease and heart failure.<br> <br> <strong>Major Research Goals--From Basic to Clinical Research</strong> <br> <strong><em>1. Find new intMMP&#x2011;2 targets and biosensors</em></strong> <br> Discovering intMMP&#x2011;2 protein targets is key to fully understanding its biological actions. Unbiased approaches have identified at least 99 high-probability intracellular targets for MMP&#x2011;2. I will develop specific, sensitive diagnostics for intMMP&#x2011;2 activity based on peptide biosensors, using identified cleavage sequences from known targets. Transfecting these constructs into cells will allow detection of intMMP&#x2011;2 activity in real time. Fragments of MMP&#x2011;2 targets will be tested as heart disease biomarkers. These tools will accelerate understanding of MMPs in all biomedical fields.<br> <br> <strong><em>2. Develop specific inhibitors of intMMP&#x2011;2</em></strong> <br> I can express intMMP&#x2011;2 in sufficient amounts for crystallization and 3D structure determination. Crystallographic data will be used to design specific intMMP&#x2011;2 inhibitors as lead compounds for more effective drugs to treat heart disease.<br> <br> <strong><em>3. Determine roles of MMP&#x2011;2 in subcellular organelles</em></strong> <br> I discovered that MMP&#x2011;2 is localized to the sarcomere, nuclei, and mitochondria. I will determine the roles and substrates of MMP&#x2011;2 in these organelles, revealing new biological actions of MMP&#x2011;2 in gene activation, Ca2+ handling, metabolism, apoptosis, and inflammation.<br> <br> <strong><em>4. Perform clinical trials of MMP inhibitors in ischemic and anthracycline-induced heart failure</em></strong> <br> A safe, effective, and inexpensive MMP inhibitor exists: sub-antimicrobial dosage doxycycline (Doxy), approved for chronic treatment of periodontitis. I will test if Doxy preferentially inhibits intMMP&#x2011;2, as I suspect. Clinical trials will test whether Doxy reduces heart failure caused by: a) adverse remodeling after myocardial infarct, and b) anthracycline-class anticancer drugs.<br> <br> <strong>Expertise</strong> <br> My lab has the expertise necessary to carry out most of these studies, including clinical trials. Synergies in my overall research impact and health outcomes will be obtained by a strong team of established collaborators to carry out these goals.<br> <br> <strong>Benefiting Health</strong> <br> MMP&#x2011;2 inhibitors, Doxy included, have great potential to reduce the burden of ischemic heart disease and heart failure, which affect thousands of Canadians. My research will lead to specific MMP&#x2011;2 inhibitors with fewer side-effects and therapeutic potential for conditions beyond heart disease.<br> <br> <strong>Mentoring</strong> <br> I have an excellent track record of training the next generation of cardiovascular scientists and physicians and fostering the careers of young, independent scientists. They enjoy the benefits of my bench-to-bedside research program through which they are exposed to an active, international research environment of physicians and basic scientists.</p> </body> </html>