Heart valve replacement is the second most common cardiac surgery in the United States and aortic valve sclerosis occurs in >25% of aged individuals. The majority of the aortic valves that are replaced also have congenital malformations establishing a link between abnormal valve development and degenerative valve disease. Wnt/b-catenin and Notch signaling pathways are among those identified as critical for valve development and are also associated with aortic valve disease. However, the roles of these regulatory pathways in heart valve cell lineage diversification, stratification, gene expression, and function have not yet been fully elucidated. Likewise the relative contributions and intersecting mechanisms of these pathways in pathologic aortic valve calcification are not known. We hypothesize that the balance of Wnt/b-catenin and Notch signaling controls normal valve stratification during development and contributes to pathologic aortic valve calcification in adults. The proposed in vivo mechanistic studies of valve lineage development and pathogenesis will be used to dissect the molecular contributions of Wnt and Notch signaling pathways to heart valve development and disease.
The aims are: 1) Determine if Wnt signaling promotes aortic valve fibrosa cell lineage differentiation and leaflet stratification in vivo. 2) Dissect the intersection of Wnt and Notch signaling pathways in aortic valve stratification and differentiation. 3) Determine if Wnt signaling promotes and Notch signaling inhibits adult aortic valve disease. We predict that the identification of signal transduction mechanisms involved in valve development and pathogenesis will point to new therapeutic approaches for these clinically significant conditions. The long-term goals of these studies are the definition of critial regulatory pathways in heart valve maturation and the identification of inhibitors of valve disease progression.

Public Health Relevance

Heart valve malformations are among the most common types of birth defects, and adult valve disease is a significant cause of morbidity and mortality i the United States. There are currently no pharmacologic- based treatments for aortic valve disease. We predict that the identification of signal transduction mechanisms involved in valve development and pathogenesis will point to new therapeutic approaches for these clinically significant conditions. The long-term goals of these studies are the definition of critical regulatory pathways in heart valve maturation and the identification of inhibitors of valve disease progression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094319-04
Application #
8457110
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Evans, Frank
Project Start
2009-07-01
Project End
2016-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$364,140
Indirect Cost
$126,140
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Mead, Timothy J; Yutzey, Katherine E (2012) Notch pathway regulation of neural crest cell development in vivo. Dev Dyn 241:376-89
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Wirrig, Elaine E; Hinton, Robert B; Yutzey, Katherine E (2011) Differential expression of cartilage and bone-related proteins in pediatric and adult diseased aortic valves. J Mol Cell Cardiol 50:561-9
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Lincoln, Joy; Yutzey, Katherine E (2011) Molecular and developmental mechanisms of congenital heart valve disease. Birth Defects Res A Clin Mol Teratol 91:526-34

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