Grant: Project Grant

Hardening of the arteries leads to heart disease and stroke, and therefore, is a major health burden for Canadians. Blood cholesterol has an important role in the development of this disease and is an important target for therapies aimed at reducing heart attacks and stroke. Cholesterol is a fat and does not, by itself, dissolve in the watery environment of the blood. Instead, it is carried in the blood packaged in specialized structures called lipoproteins. Two types of lipoproteins that have the most influence on hardening of the arteries, and therefore heart disease and stroke, are LDL (the bad cholesterol) and HDL (the good cholesterol). High levels of LDL cholesterol in the blood support the development of hardening of the arteries and treatment efforts have been aimed at reducing LDL cholesterol. On the other hand, high levels of HDL cholesterol counteract hardening of the arteries because HDL both prevents and reverses cholesterol build up in the arteries. Treatments centered on HDL have so far been aimed at increasing HDL levels, without regarding HDL function. This application is aimed at understanding the role of a novel cellular factor, PDZK1, in mediating beneficial functions of HDL in cells within atherosclerotic plaques, which can both halt the development and even reverse the growth of the plaques. We will carry out our studies using laboratory mice engineered to develop atherosclerosis when fed a fatty diet. Moreover, these mice are engineered to lack or express PDZK1 in specific tissues which will allow us to tease apart how it protects against atherosclerosis and its role in protection brought about by HDL. Understanding how HDL brings about reversal or "regression" of atherosclerosis will pave the way to identifying new pathways that can be potential targets for treatment.