Grant: Project Grant

Blood clots associated with heart disease are the major cause of death and morbidity in Canada, and they exact high personal, community and health care costs. A number of risk factors are known to accelerate heart disease, including smoking, diabetes, hypertension, and obesity. My research laboratory has had a long-standing interest in the pathological role of endoplasmic reticulum (ER) stress in heart disease. Of particular interest is the role of the 78-kDa glucose regulated protein (GRP78) in the development and progression of heart disease and blood clots. We have now reported that both patients and mice that have heart disease produce autoantibodies in their blood against GRP78. These autoantibodies can accelerate the early stages of heart disease by increasing the binding of monocytes to lesion-resident endothelial cells. Furthermore, we have shown that this binding of monocytes to the endothelium involves the activation of a specific cellular factor termed NF-kappaB. It is known that NF-kappaB accelerates heart disease, suggesting a mechanistic link between the anti-GRP78 autoantibody/cell surface GRP78 complex and atherothrombotic disease. Although we have demonstrated that anti-GRP78 autoantibodies accelerate the progression of atherosclerosis, we have yet to determine whether this mechanism (i) increases the development of blood clots associated with atherosclerosis and (ii) involves NF-kappaB activation. This research proposal will allow us to determine the contribution of these autoantibodies to the development of blood clots associated with atherosclerosis. In addition, we have identified novel small molecules that target GRP78 which could represent new medicines having the ability to treat heart disease and blood clots.