Grant: Project Grant

In this renewal study we wish to continue to investigate how readily we can interfere with the accumulation of cholesterol in blood vessels to improve outcomes of heart disease using a novel therapeutic antibody. The novel antibody has been shown to bind to sugar chains inside blood vessels and block cholesterol accumulation in animal models of heart disease and cardiovascular risk (CVD). During diabetes there are more sugar chains being produced that contribute to increased heart disease and CVD risk. The primary objectives of this proposal are to assess the efficacy of the novel antibody to benefit heart disease development in animal models of insulin resistance as well as larger animal models needed for pre-clinical trials. We will employ pre-clinical models (rodent, rabbit and swine) of hyper cholesterolemia and/or insulin resistance. We will test the efficacy of the novel antibody to block the accumulation of cholesterol rich lipids. We wish to understand the biochemical and molecular target sites of the antibody. We will also test the ability of the novel antibody to mount a healthy 'immunogenic' response that could mimic a vaccine and become more effective long term. New data suggests that remnant cholesterol may preferentially accumulate in human tissue, more so than for LDL and is beginning to change lipid guidelines for physicians. Work by our group also suggests that this is the case in numerous animal models of CVD and insulin resistance. We also have generated new data using the highly specific next generation antibodies (called 'idiotypic' antibodies, which act like a vaccine) against connective tissue in blood vessels that entrap cholesterol, that could potentially inhibit the accumulation of remnant particles. Only very few groups around the world have access to this new antibody. Primary objectives include collecting data to prevent and reverse heart disease so that we obtain approvals for human clinical trials.