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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111770-02
Application #
8521363
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Evans, Frank
Project Start
2012-08-03
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$568,927
Indirect Cost
$228,252
Name
Albert Einstein College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Han, Pei; Li, Wei; Lin, Chiou-Hong et al. (2014) A long noncoding RNA protects the heart from pathological hypertrophy. Nature 514:102-6
Bell, Robert D; Long, Xiaochun; Lin, Mingyan et al. (2014) Identification and initial functional characterization of a human vascular cell-enriched long noncoding RNA. Arterioscler Thromb Vasc Biol 34:1249-59
Chamberlain, Alyssa A; Lin, Mingyan; Lister, Rolanda L et al. (2014) DNA methylation is developmentally regulated for genes essential for cardiogenesis. J Am Heart Assoc 3:e000976
Yang, Jin; Zeini, Miriam; Lin, Chieh-Yu et al. (2014) Epicardial calcineurin-NFAT signals through Smad2 to direct coronary smooth muscle cell and arterial wall development. Cardiovasc Res 101:120-9
Wang, Yidong; Wu, Bingruo; Chamberlain, Alyssa A et al. (2013) Endocardial to myocardial notch-wnt-bmp axis regulates early heart valve development. PLoS One 8:e60244