Notch signaling in heart valve development and disease

心脏瓣膜发育和疾病中的Notch信号传导

• 批准号: 7851332
• 负责人: Katherine E Yutzey
• 金额: $ 45.41万
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851332
• 关键词: Adenoviruses; Adult; Apolipoprotein E; Binding; Birds; Cardiac Surgery procedures; Cartilage; Cell Culture Techniques; Cell Lineage; Characteristics; Congenital Abnormality; Congenital Heart Defects; Connective Tissue Cells; Development; Disease; Disease Progression; Elastin; Genes; Goals; Growth Factor; Heart; Heart Valves; Homeostasis; Individual; Link; Molecular; Morbidity - disease rate; Morphogenesis; Mus; Notch Signaling Pathway; Osteoblasts; Pathogenesis; Pathologic; Pathway interactions; Pattern; Prevention; Process; Regulatory Pathway; Research; Role; Sclerosis; Signal Transduction; Small Interfering RNA; Stem cells; Stratification; Structure; System; Tendon structure; United States; aged; aortic valve; aortic valve disorder; bone; bone cell; calcification; gain of function; genetic association; heart valve replacement; in vivo; inhibitor/antagonist; interstitial cell; loss of function; malformation; mineralization; mortality; notch protein; novel therapeutics; osteogenic; public health relevance; semilunar valve

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.

描述（由申请人提供）：心脏瓣膜置换是美国第二常见的心脏手术，主动脉瓣硬化/钙化发生在> 25％的老年人中。替换的大多数主动脉瓣也具有先天性畸形，在异常瓣膜发育与退化瓣膜疾病之间建立了联系。 Notch1是当前与先天性心脏半道路瓣膜畸形以及老年人中病理主动脉瓣钙化相关的唯一基因。除了最初的遗传关联外，尚未确定Notch信号传导在心脏瓣膜发育和稳态中的细胞和分子功能。我们假设半道路瓣膜谱系发育需要Notch信号传导，并抑制成年人的病理主动脉瓣钙化。小鼠和鸟类系统中瓣膜谱系发育和发病机理的拟议机理研究将剖析Notch信号传导的细胞和分子机制，并在心脏瓣膜发育和疾病中相交。目的是：1。确定Notch信号是否调节体内半路段细胞谱系分化和小叶分层。 2。在主动脉瓣祖细胞谱系发育和间质细胞的成骨潜力中剖析缺口信号通路和相交途径。 3。确定Notch信号是否抑制成人主动脉瓣钙化，以及缺口信号的损失是否有助于体内瓣膜疾病。在成人瓣膜钙化过程中，Notch1信号对瓣膜形态发生以及抑制作用至关重要的鉴定可以在预防和治疗最常见的先天性心脏畸形和成人瓣膜疾病时开放新的治疗途径。这些研究的长期目标是心脏瓣膜细胞谱系中关键调节途径的定义以及鉴定瓣膜疾病进展抑制剂的定义。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先天缺陷类型之一，成人主动脉瓣疾病是美国发病率和死亡率的重要原因。我们的研究将检查特定的分子途径，Notch信号通路及其在正常瓣膜发育和成人瓣膜疾病中的作用。