Heart valve replacement is the second most common cardiac surgery in the United States and aortic valve sclerosis/calcification 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. Notch1 is the only gene currently associated with congenital heart semilunar valve malformations as well as pathologic aortic valve calcification in older individuals. Aside from the initial genetic association, the cellular and molecular functions of Notch signaling in heart valve leaflet development and homeostasis have not been determined. We hypothesize that Notch signaling is required for semilunar valve cell lineage development and inhibits pathologic aortic valve calcification in adults. The proposed mechanistic studies of valve lineage development and pathogenesis in mouse and avian systems will dissect the cellular and molecular mechanisms of Notch signaling and intersecting pathways in heart valve development and disease.
The Aims are: 1. Determine if Notch signaling regulates semilunar valve cell lineage differentiation and leaflet stratification in vivo. 2. Dissect the Notch signaling pathway and intersecting pathways in aortic valve progenitor cell lineage development and interstitial cell osteogenic potential. 3. Determine if Notch signaling inhibits adult aortic valve calcification and if loss of Notch signaling contributes to valve disease in vivo. The identification of Notch1 signaling as critical for valve morphogenesis as well as inhibitory in the adult valve calcification process could open new therapeutic avenues in the prevention and treatment of the most common forms of congenital heart malformations and adult valve disease. The long term goals of these studies are the definition of critical regulatory pathways in heart valve cell lineage development and the identification of inhibitors of valve disease progression.
Congenital malformations in heart valve development are among the most common types of birth defects and adult aortic valve disease is a significant cause of morbidity and mortality in the United States. Our studies will examine a specific molecular pathway, the Notch signaling pathway, and its role in normal valve development and adult valve disease.
|Hulin, Alexia; Moore, Vicky; James, Jeanne M et al. (2017) Loss of Axin2 results in impaired heart valve maturation and subsequent myxomatous valve disease. Cardiovasc Res 113:40-51|
|Fang, Ming; Xiang, Fu-Li; Braitsch, Caitlin M et al. (2016) Epicardium-derived fibroblasts in heart development and disease. J Mol Cell Cardiol 91:23-7|
|Wirrig, Elaine E; Gomez, M Victoria; Hinton, Robert B et al. (2015) COX2 inhibition reduces aortic valve calcification in vivo. Arterioscler Thromb Vasc Biol 35:938-47|
|Wirrig, Elaine E; Yutzey, Katherine E (2014) Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler Thromb Vasc Biol 34:737-41|
|Fang, Ming; Alfieri, Christina M; Hulin, Alexia et al. (2014) Loss of ?-catenin promotes chondrogenic differentiation of aortic valve interstitial cells. Arterioscler Thromb Vasc Biol 34:2601-8|
|Braitsch, Caitlin M; Yutzey, Katherine E (2013) Transcriptional Control of Cell Lineage Development in Epicardium-Derived Cells. J Dev Biol 1:92-111|
|Cheek, Jonathan D; Wirrig, Elaine E; Alfieri, Christina M et al. (2012) Differential activation of valvulogenic, chondrogenic, and osteogenic pathways in mouse models of myxomatous and calcific aortic valve disease. J Mol Cell Cardiol 52:689-700|
|Le, Tien T; Conley, Kevin W; Mead, Timothy J et al. (2012) Requirements for Jag1-Rbpj mediated Notch signaling during early mouse lens development. Dev Dyn 241:493-504|
|Braitsch, Caitlin M; Combs, Michelle D; Quaggin, Susan E et al. (2012) Pod1/Tcf21 is regulated by retinoic acid signaling and inhibits differentiation of epicardium-derived cells into smooth muscle in the developing heart. Dev Biol 368:345-57|
|Mead, Timothy J; Yutzey, Katherine E (2012) Notch pathway regulation of neural crest cell development in vivo. Dev Dyn 241:376-89|
Showing the most recent 10 out of 20 publications