Grant: Operating Grant

Heart failure is a common and devasting condition with high morbidity and mortality. Pressure-overload occurs in common clinical scenarios such as hypertension and coronary artery disease leads to heart attacks which are the major causes of heart failure. Our research will tackle and elucidate the precise role of PI3 kinase (PI3K) isoforms in the control of the heart under these stressors. PI3K is an enzyme that adds a phosphate group to a lipid molecule involved in signalling to generate an active chemical called phosphatidylinositol (3,4,5)-trisphosphate (abbreviated PIP3). There are three major isoforms of PI3K: alpha, beta and gamma. Changes in PI3K signaling are a key finding in heart failure. Previous studies in this field of investigation have utilized non-specific pharmacological blockers of PI3K which coupled with the fact that they can only be used on a short-term basis limits the conclusions that can be drawn from these studies. We will for the first time appreciate the unique and distinct roles of the different classes of PI3K in heart disease. We have the unique opportunity to combine the findings obtained from four genetically engineered murine models with a thorough set of in vivo and in vitro investigations. Our studies employ in vivo experimental models (pressure-overload and heart attacks) and functional assays and thus provide pre-clinical data for novel therapeutic interventions in heart disease. We can begin to explore the potential therapeutic and/or toxic effects of blocking or enhancing specific isoforms of PI3K in heart disease. Indeed, the pharmaceutical industry has successfully targeted these specific isoforms as novel anti-cancer and anti-inflammatory agents. These agents may indeed have important cardiac toxicity.