Grant: Project Grant

Atherosclerotic cardiovascular disease (ASCVD) causes 28% of deaths across Canada and represents the #1 cause of mortality worldwide. Preventive and therapeutic efforts (exercise, smoking cessation, diet, reduction of LDL-C, control of diabetes and treatment of hypertension) have had a major beneficial impact on the health of Canadians. Yet, the burden of disease remains considerable. Attempts to harness the properties of high density lipoproteins (HDL- the "good" cholesterol) to reduce the risk of ASCVD have failed in large clinical trials. HDL removes cholesterol from the arterial wall but this pathway remains untapped. We have found a protein, desmocollin 1 (DSC1) that prevents the removal of cholesterol from cells and is found in large quantities in human atherosclerosis lesions. Our laboratory work indicates that blocking this pathway is feasible and may provide benefit to prevent fatty buildup in arteries. We have found an inhibitor of DSC1 by virtual screening of over 10 million pharmacological compounds. Our top candidate, Docetaxel is an FDA approved drug for cancer treatment. We found that Docetaxel inhibits DSC1 in minute quantities (0.7 nonomolar), a concentration much lower that used in cancer treatment. We will first study Docetaxel in the laboratory using cholesterol-laden cells (similar to the ones found in the atherosclerotic plaque) and determine optimal conditions. Then, we will study the effects of Docetaxel in preventing atherosclerosis in an early-stage mouse model, but also to treat atherosclerosis in a late-stage model of atherosclerosis. In a separate objective, we will measure DSC1 levels in the blood of patients with heart attacks and healthy individuals to determine whether DSC1 levels can be a biomarker of atherosclerosis. These studies will pave the way for first-in-man trials of very low dose Docetaxel to prevent and treat atherosclerosis.