研究领域

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Cardiovascular complications are the major problem for people with both type 1 and type 2 diabetes. Diabetic patients have a greater incidence of hypertension, congestive heart failure, atherosclerosis and circulatory disturbances than people without diabetes, and in addition develop a specific form of heart dysfunction called diabetic cardiomyopathy. Dr. MacLeod's lab is interested in understanding the reasons for the greater cardiovascular dysfunction in diabetic patients, with the goal of identifying potential therapeutic targets. Changes in many cellular mechanisms have been identified in cardiovascular tissues in diabetes. The lab's goal is to identify changes in the intracellular signaling pathways that regulate cardiac and vascular contraction. To do so, investigations range from the subcellular to the whole animal level, and encompass techniques including biochemical analysis, mass spectroscopy, electron, confocal and fluorescence microscopy, wire myography, and together with lab collaborators, measurements of blood pressure (both indirect and direct) and cardiac function, at the level of myocytes, whole hearts and whole animals (echocardiography). Recently, Dr. MacLeod's lab has focused on the significance of activation of the RhoA/ROCK pathway in the contractile dysfunction associated with diabetic cardiomyopathy. The lab has found that this pathway is activated in cardiomyocytes from a diabetic rat model, and surprising, that acute inhibition of ROCK improves contractile function of diabetic hearts both in vivo and in vitro. Current research is directed towards understanding the underlying mechanisms contributing to increased activation of the pathway, and the ways in which over-activation of the pathway impairs cardiac contractility in diabetes. In other work, the lab is studying the consequences of diabetic-induced activation of protein kinase C, particularly PKCb2 in cardiovascular tissues. Increased activation of PKCb2 has been implicated in the cardiovascular complications of diabetes, but its downstream targets have not been well studied. The lab has found that this isoform of PKC is present in mitochondria from diabetic rat hearts, where it appears to modulate the activity of some mitochondrial proteins. Dr. MacLeod's lab is currently identifying the mitochondrial targets of PKCb2 and the consequences of the changes in their activity to mitochondrial and cardiac function in diabetes.