Grant: Foundation Grant

<html> <body> <p> <strong>Background</strong> </p> <p>A hallmark of many age-related, chronic inflammatory disorders is the dysregulated release of proteases into the extracellular milieu. We have identified a role for Granzyme (<u>Gran</u>ule-secreted en<u>zyme</u>) serine proteases in aging and chronic tissue injury and repair. While once thought to be only involved in lymphocyte-induced killing, our research has challenged this paradigm. Indeed, granzymes are produced by many types of cells, function both intracellularly or extracellularly in disease, and contribute to tissue injury, inflammation, and disrepair.^1-14 Granzymes are highly elevated in conditions characterized by aging and/or repetitive cycles of injury and repair. There are 5 granzymes in humans: GzmA, B, H, K and M. Much of our research has focused on GzmB validation as a therapeutic target where we have shown that it contributes to extracellular matrix degradation and pathology of the vessels (atherosclerosis, aneurysm, permeability), lung (COPD, emphysema) and skin (aging, wound healing). While significant progress has been made, there remains much that we do not understand.<br> </p> <p> <strong>Major Questions to be addressed:</strong> <br> 1. How/why GzmB is induced and what is the patho/physiological significance?<br> 2. How does GzmB contribute to tissue damage/dysfunction and/or promote or impede tissue repair?<br> 3. How can therapeutics targeting GzmB be best exploited to treat disease?<br> 4. What are the functions of other human granzymes in health and disease?<br> 5. Using our disease modeling expertise, what other proteins contribute to aging and impaired healing?<br> </p> <p> <strong>Clinical Relevance/Core Expertise:</strong> <br> My research platform covers the transition from discovery through to target validation, drug discovery, proof-of-concept, technology transfer, commercialization and clinical application. The type of injury and how GzmB impacts tissue repair is context-dependent, depending on the disease, where GzmB is localized and the source of its production.As such,I have utilized established connections with other scientists, anatomic pathologists, pharmaceutical, and clinical specialists to understand the clinical problems/unmet needs and clinical context of disease manifestation in order to best guide how we approach our investigations and progress towards the clinic. In support of our strategy, we have developed inhibitors that are being tested in our models with the ambitious goal of entering Phase I clinical trials within the next few years.<br> </p> <p> <strong>Training and Mentoring:</strong> <br> In a recent report from the Conference Board of Canada (CBC), ~60% of PhDs hold jobs outside of academia. A recommendation was put forward from CBC and NIH for academia to do more to prepare students for non-academic careers. Future graduates will benefit from experiences that incorporate basic science with clinical application as well as other entrepreneurial skills. Trainees will be exposed to integrated mentoring from academic, clinical, technology transfer and industry experts as to how/if their science fits into the larger continuum<strong><em>.</em></strong> In support, I co-Direct and/or am involved with 3 CIHR Strategic Training in Health Research (STIHR) programs in cardiovascular/pulmonary, skin and transplantation. All of these programs focus on integrating basic science with clinical expertise and application. Moving forward, in addition to promoting high quality, biomedical research, my program will continue to foster entrepreneurialism, venture creation, and other areas that are underemphasized in academic training programs.</p> </body> </html>