Wnt signaling in heart valve development and disease

心脏瓣膜发育和疾病中的 Wnt 信号传导

• 批准号: 8457110
• 负责人: Katherine E Yutzey
• 金额: $ 36.41万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457110
• 关键词: Adult; Cardiac Surgery procedures; Cartilage; Cell Lineage; Collagen; Congenital Abnormality; Development; Disease; Disease Progression; Disease model; Elastin; Equilibrium; Exons; Extracellular Matrix; Functional disorder; Gene Expression; Genes; Goals; Heart; Heart Valve Diseases; Heart Valves; Human; Individual; Link; Molecular; Morbidity - disease rate; Mus; Mutagenesis; Mutation; NOTCH1 gene; Notch Signaling Pathway; Notch and Wnt Signaling Pathway; Osteogenesis Imperfecta; Pathogenesis; Pathologic; Pathway interactions; Prevention strategy; Regulation; Regulatory Pathway; Relative (related person); Role; Sclerosis; Signal Transduction; Stratification; United States; aged; aortic valve; aortic valve disorder; base; calcification; clinically significant; gain of function; gene interaction; heart valve replacement; in vivo; inhibitor/antagonist; interstitial cell; loss of function; malformation; mortality; mouse model; notch protein; novel therapeutic intervention; prevent; standard care

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.

描述（由申请人提供）：心脏瓣膜置换术是美国第二常见的心脏手术，主动脉瓣硬化发生在>25%的老年人中。大多数被置换的主动脉瓣也有先天性畸形，这在异常瓣膜发育和退行性瓣膜疾病之间建立了联系。Wnt/β-连环蛋白和Notch信号通路是被确定为对瓣膜发育至关重要的信号通路之一，并且也与主动脉瓣疾病相关。然而，这些调节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，这些通路在病理性主动脉瓣钙化中的相对作用和交叉机制也不清楚。我们假设Wnt/b-连环蛋白和Notch信号的平衡控制了发育过程中正常的瓣膜分层，并促进了主动脉瓣的病理性钙化。 成年人了所提出的瓣膜谱系发育和发病机制的体内机制研究将用于剖析Wnt和Notch信号通路对心脏瓣膜发育和疾病的分子贡献。目的是：1）确定Wnt信号传导是否促进体内主动脉瓣纤维化细胞谱系分化和瓣叶分层。2)剖析Wnt和Notch信号通路在主动脉瓣分层和分化中的交叉点。3)确定Wnt信号是否促进和Notch信号是否抑制成人主动脉瓣疾病。我们预测，识别参与瓣膜发育和发病机制的信号转导机制将为这些临床重要疾病提供新的治疗方法。这些研究的长期目标是确定心脏瓣膜成熟的关键调节途径和识别瓣膜疾病的抑制剂 进展