Supravalvular aortic stenosis (SVAS) is an inherited disorder that causes hemodynamically significant narrowing of the ascending aorta and other elastic arteries. Human genetic studies suggest that a reduction in elastin gene (ELN) expression causes SVAS. To prove that ELN is responsible for SVAS and to enable testing of new treatments, a murine model of SVAS will be developed using gene-targeting by homologous recombination. Two models will be made. The first deletes an ELN allele and the second truncates an ELN allele, testing whether loss of function or dominant negative ELN mutations can cause SVAS. Developmental studies will determine the mechanism by which ELN mutations induce vascular disease. Our primary hypothesis is that ELN mutations disrupt elastic fibers in the medial layer, making the vasculature inelastic and susceptible to recurrent injury and repair. Demonstration that the initial step in SVAS is damage to medial elastic fibers followed by recurrent inflammation and fibrosis will support this hypothesis. Alternative mechanisms will be tested and include: increased mechanical stress caused by vascular inelasticity stimulates smooth muscle hypertrophy and proliferation; defective barrier function of the internal elastic lamina promotes intimal inflammation causing stenosis; mutations in ELN interferes with cellular migration during vasculogenesis leading to stenosis. If our primary hypothesis is correct then ELN expression or decreasing hemodynamic stress should ameliorate disease. The effect of beta adrenergic antagonists to reduce hemodynamic stress and vitamin D to modulate ELN expression on SVAS will be examined in our animal model. In addition, techniques of maternal gene therapy to correct elastogenesis and prevent SVAS in progeny will be tested. These approaches may have implications for the treatment of human vascular diseases. Finally, this model enables us to test whether ELN mutations act in synergy with hypertension or hypercholesterolemia to promote vascular disease by mating our SVAS model with mice deficient in atrial naturietic peptide or low density lipoprotein receptor. Demonstration of synergy will support a role for ELN in common vascular disease and stimulate the search for human correlates. The University of Utah provides Dr. Dean Li a unique opportunity to learn cardiovascular molecular genetics from Dr. M. Keating and animal modeling through gene-targeting from Dr. M. Capecchi. The NHLBI Clinician Scientist Award will develop the candidate into an independent investigator.
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