The genetics of cardiovascular disease using both the human and the mouse as a model system.
Over the course of the past 18 years at Duke, we have identified the causative genes for a number of different Mendelian disorders of vascular malformations. In addition to continuing our molecular analysis of mutations in these patients, we have generated animal models to further understand the disease pathogenesis and to generate and test new therapies.
In other projects we have harnessed the power of mouse genetics to map novel genes that affect the severity and progression of disease in mouse models of more common cardiovascular disease (eg. stroke and heart disease). We begin with an animal model of the disease, such as a surgically induced or transgenic model of disease. The surgical intervention or the transgene acts as a sensitizer to create the disease in the animals. These sensitized models often exhibit drastically different rates of disease progression or outcome depending on the inbred strain employed. Using genetic crosses with the sensitizer, we can map the loci that influence disease outcome. We call these risk factors “modifier loci” since they modify disease progression or outcome. The orthologs of the modifier genes discovered in the mouse models are then investigated in the corresponding human disease populations.