Wnt signaling in heart valve development and disease

描述（由申请人提供）：心脏瓣膜置换术是美国第二大最常见的心脏手术，主动脉瓣硬化发生在25%的老年人中。大多数被替换的主动脉瓣也有先天性畸形，这在瓣膜异常发育和退行性瓣膜疾病之间建立了联系。Wnt/b-catenin和Notch信号通路被认为对瓣膜发育至关重要，也与主动脉瓣疾病有关。然而，这些调控途径在心脏瓣膜细胞谱系多样化、分层、基因表达和功能中的作用尚未完全阐明。同样，这些途径在病理性主动脉瓣钙化中的相对作用和交叉机制尚不清楚。我们假设Wnt/b-catenin和Notch信号的平衡控制着发育过程中的正常瓣膜分层，并有助于主动脉瓣的病理性钙化

DESCRIPTION (provided by applicant): 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.