DESCRIPTION (provided by applicant): Calcific aortic valve stenosis (CAVS) is the most common disease needed surgical valve replacement. Recent studies in human patients indicate that, rather than a senile or degenerative disease; CAVS is an active complex syndrome involving multiple cellular processes. Common cardiovascular risk factors, including age, gender, abnormal lipoprotein/cholesterol profile, hypertension, and type II diabetes are all associated with CAVD; however, the association is weak in patients over 65 years old, who have the greatest risk of progressing to aortic valve stenosis. In contrast, congenital valve abnormalities markedly increase the risk. Nearly half of the patients with aortic stenosis have a bicuspid aortic valve (BAV), the most common congenital cardiac malformation affecting 0.6% of the population. Significantly, BAV patients develop a form of rapidly progressive CAVS at an earlier age, suggesting that genetic factors are involved in the disease. However, the patients with the early stages of CAVD are symptomless and unavailable for human studies, whereas the study of the latter stages of CAVD patients is unlikely to reveal the underlying molecular mechanisms of CAVS. To fill this gap, we have developed novel mouse models of human CAVS. The overall goal of this project is to use these models to characterize the genetic pathways that regulate aortic valve biology and mediate CAVS. In this program, we will use these new models to examine whether Egfr, Notch1, and Nfatc1 forms a genetic network that maintains the biology of the aortic valve and mediate CAVS in three Aims. Aim 1 will determine if Notch1 and Egfr signalings interact in the VECs to maintain endothelial integrity. Aim 2 will define if Egfr protects valve from early sclerosis through Nfatc1 in the VECs. Aim 3 will identify the common downstream effectors of Notch1, Nfatc1, and Egfr involved in CAVS. Because of their central roles in differentiation, survival, and proliferation, we believe that the newly identified interactions among Egfr, Notch1, and Nfatc1 and their common downstream targets will provide novel molecular insights into the pathogenesis of CAVS. The information would have direct implications in the development of new therapeutic strategies for this most common valve disease. PUBLIC HEALTH RELEVANCE: The goal of this project is to study cellular and molecular mechanisms of calcific aortic valve stenosis by using newly generated mouse models of the disease. Completion of the project will provide critical information on the underlying pathogenesis of human calcific aortic valve stenosis thereby helping develop new therapeutic and preventive strategies for this devastating human disease.
|Effective start/end date||8/3/12 → 6/30/17|
- National Heart, Lung, and Blood Institute: $490,539.00
- National Heart, Lung, and Blood Institute: $98,108.00
- Cardiology and Cardiovascular Medicine
- Molecular Biology