A series of epidemiological studies have revealed a consistent association of circulating C-reactive protein (CRP) levels with risk of ischemic cardiovascular disease among apparently healthy individuals. CRP may have great clinical values on cardiovascular risk assessment and early prevention, and its underlying pathological mechanisms may provide novel therapeutic strategies. However, further application of CRP on clinical practice is hampered by a key issue -- whether CRP is a direct risk mediator for cardiovascular disease or it is merely an innocent bystander. Due to the inherent limitations of in vitro experiments on the CRP study, in vivo study on suitable animal models has become essential to address this issue. We propose to create a transgenic rat model that over-expresses the human CRP gene in the liver. Our selection of rats rather than mice is based on recent observations from the CRP transgenic mice and the CRP intraperitoneally injected rats. Compared with intraperitoneal injection, transgenic over-expression offers a long-term and stable elevation of human CRP in the rats. Specifically, we will (1) generate ALB-hCRP transgenic rats driven by the albumin enhancer/promoter;and (2) perform a pilot phenotype characterization of ALB-hCRP transgenic rats on systematic inflammation, endothelial activation and vascular lesion formation. We anticipate that this animal model will provide an in vivo platform for exploring the CRP pathological role in the development of cardiovascular disease. It will also provide a platform for screening and testing new preventive and therapeutic strategies for cardiovascular disease based on new understandings of the CRP biology.

SC2HL095098

2008-08-01

2012-06-30