Research Project
2433889
Atherosclerosis is a leading cause of morbidity and mortality. Epidemiological and genetic data have shown convincingly: that low levels of HDL or apoAI are associated with increased risk of developing coronary heart disease (CHD). In contrast, high levels of HDL are protective against CHD and confer longevity in humans. The main objective in this proposal is to develop a new animal model of atherosclerosis by introducing the human genes encoding cholesteryl ester transfer protein (CETP) and apolipoprotein AI (apoAI) into the Dahl salt-sensitive hypertensive rat. Our novel approach here will utilize two different risk factors for atherogenesis, namely CETP and hypertension. The overexpression of the CETP gene is expected to decrease the ratio of plasma HDL to LDL, concomitant with the increased rate o development of atherosclerosis due to the hypertensive genetic background of the Dahl rat. The presence of the human apoAI transgene will facilitate the optimal activity of the human CETP. We will utilize this model to study the effect of inhibiting CETP on the progress of atherosclerosis using a rat anti-human CETP polyclonal antibody. This transgenic model should facilitate the testing of other anti- atherosclerotic agents, in the context of a hypertensive genetic background. PROPOSED COMMERCIAL APPLICATIONS Mortality and morbidity due to atherosclerosis are major health problems affecting millions of people annually. Low levels of HDL or apoAI are associated with increased risk of developing coronary heart disease. whereas high levels of HDL are protective and confer longevity in humans. The proposed transgenic CETP hypertensive/atherosclerosis rat model would be vent useful for the testing of anti-atherosclerotic CETP inhibitors, specifically peptide and DNA vaccines. Such therapeutic agents are expected to increase plasma HDL/LDL ratios. thus reducing or possibly reversing atherosclerotic lesions. The market size for these novel drugs would be very large.
