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，25%的老年人会发生主动脉瓣硬化症。大多数被替换的主动脉瓣也有先天性畸形，在瓣膜发育异常和退行性瓣膜疾病之间建立了联系。WNT/b-catenin和Notch信号通路被认为是瓣膜发育的关键信号通路之一，也与主动脉瓣疾病有关。然而，这些调控通路在心脏瓣膜细胞谱系多样化、层次化、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。我们推测，Wnt/b-catenin和Notch信号平衡在发育过程中控制正常的瓣膜分层，并促进病理性主动脉瓣钙化。 成年人。提出的瓣膜谱系发育和发病机制的体内机制研究将被用于剖析Wnt和Notch信号通路在心脏瓣膜发育和疾病中的分子贡献。其目的是：1)确定Wnt信号是否促进体内主动脉瓣纤维瘤细胞系的分化和小叶的层化。2)解剖Wnt和Notch信号通路在主动脉瓣分层分化中的交叉点。3)确定Wnt信号是否促进成人主动脉瓣病变，而Notch信号是否抑制成人主动脉瓣病变。我们预测，识别涉及瓣膜发育和发病机制的信号转导机制将为这些临床上有意义的疾病提供新的治疗方法。这些研究的长期目标是定义心脏瓣膜成熟的关键调节途径，并识别瓣膜疾病的抑制物。 进步。