Coronary Heart Disease (CHD) is a major cause of death and a common complication of diabetes, which is increasing in prevalence in the United States. Despite the frequency of CHD, there are relatively few drugs on the market that have been shown to reduce mortality. The development of therapeutics for patients that suffer from CHD has been hindered by a lack of sufficient animal models that simulate the human condition. Most models possess only a narrow subset of the characteristics of the human disease spectrum and therefore may not provide adequate venues for testing new therapeutic agents. A new mouse model, a double knockout of the SR-BI (HDL receptor) gene and the apoE gene (SR-BI/apoE dKO), has been demonstrated to possess characteristics of CHD very similar to that of humans, including, occlusive coronary artery atherosclerosis, myocardial infraction, cardiac failure and death. The CardioMouse(tm) System, which currently includes two strains of the SR-BI/apoE dKO mouse, was generated by the Krieger laboratory at the Massachusetts Institute of Technology and has been exclusively licensed to Cardium Pharmaceuticals for commercial development. The overall goals of this proposal are to develop, characterize and commercialize this technology for use in pharmaceutical discovery and product development. We will therefore: 1) optimize a breeding/production program to efficiently produce the SR-BI/apoE dKO, 2) evaluate in detail the extent to which disease progression in the SR-BI/apoE dKO mimics that of human CHD by performing a time course analysis of pathology in these mice, and 3) evaluate the effects of drug interventions on SR-BI/apoE dKO mortality. These studies are critically important for defining the utility of the CardioMouse(tm) System for the discovery and development of new therapeutics for cardiovascular disease. Ultimately, the overall goal of this research is to produce a well characterized animal model to investigate the pathogenesis of, and cure for CHD.
| Braun, Anne; Yesilaltay, Ayce; Acton, Susan et al. (2008) Inhibition of intestinal absorption of cholesterol by ezetimibe or bile acids by SC-435 alters lipoprotein metabolism and extends the lifespan of SR-BI/apoE double knockout mice. Atherosclerosis 198:77-84 |
