Notch signaling in heart valve development and disease

描述(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/钙化。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。NOTCH1是目前唯一与老年人先天性心脏半月瓣畸形和病理性主动脉瓣钙化相关的基因。除了最初的遗传关联，Notch信号在心脏瓣膜叶发育和内稳态中的细胞和分子功能尚未确定。我们假设Notch信号是半月瓣细胞谱系发育所必需的，并抑制成人病理性主动脉瓣钙化。拟开展的小鼠和禽类系统瓣膜谱系发育和发病机制研究将剖析Notch信号通路和交叉通路在心脏瓣膜发育和疾病中的细胞和分子机制。其目的是：1.确定Notch信号是否调节体内半月瓣细胞系的分化和小叶的层化。2.解剖Notch信号通路和交叉性通路在主动脉瓣祖细胞系发育和间质细胞成骨潜能中的作用。3.确定Notch信号是否抑制成人主动脉瓣钙化，以及Notch信号的缺失是否在体内导致瓣膜疾病。鉴定Notch1信号对瓣膜形态发生以及成人瓣膜钙化过程的抑制至关重要，这可能为预防和治疗最常见的先天性心脏畸形和成人瓣膜疾病开辟新的治疗途径。这些研究的长期目标是定义心脏瓣膜细胞谱系发育中的关键调控途径，并识别瓣膜疾病进展的抑制因素。公共卫生相关性：心脏瓣膜发育中的先天性畸形是最常见的出生缺陷类型之一，成人主动脉瓣疾病是美国发病率和死亡率的重要原因。我们的研究将考察一种特定的分子途径，即Notch信号通路，以及它在正常瓣膜发育和成人瓣膜疾病中的作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.