Adhesive signaling in aortic valve development and disease

 描述（由申请人提供）：钙化性主动脉瓣疾病（CAVD）是一种日益普遍且危及生命的疾病，目前尚无临床上有用的生物靶点或治疗药物。最近几项引人注目的研究已经确定了主动脉瓣形成和钙化性主动脉瓣狭窄中存在的共同信号通路，但我们对这些信号如何在细胞和组织水平上整合和协调的理解非常有限。控制瓣膜原基伸长、浓缩和基质分层的细胞机制具有最高的临床重要性，但几乎完全未知。更复杂的问题是，这些形态发生和重塑行为发生在动态力学环境中，由于缺乏研究工具，其影响一直难以调查。钙粘蛋白-11是一种细胞-细胞粘附蛋白，其调节集体间充质细胞迁移及其随后向成骨谱系的分化，使其成为调节瓣膜形成和稳态的有吸引力的候选者。钙粘蛋白-11在内皮细胞和内皮细胞垫的间充质中强烈且特异性地表达，但随着垫伸长成瓣膜，在间充质中逐渐降级。该提案中的初步数据表明，钙粘蛋白-11的缺失导致关键瓣膜重塑期间的显著致死性。相反，CDH 11的瓣膜特异性过表达是可行的，但具有增厚的主动脉瓣，具有在人类CAVD中观察到的典型病变的细胞间质聚集和钙化区域。该建议将测试以下假设：紧密范围的钙粘蛋白-11表达对于胎儿瓣膜细胞化、重塑和成熟的长期稳态功能的适当协调是必不可少的。该提案的第一个目的是确定钙粘蛋白-11在胚胎主动脉瓣细胞化和重塑中的机械生物学作用。目标2将测试钙粘蛋白11如何调节出生后瓣膜重塑和钙化。该提案的目标3将测试钙粘蛋白-11再平衡是否可以挽救和/或预防主动脉瓣CHD和/或钙化的发展。这项研究的结果将阐述一种新的严格控制和机械敏感的机制，负责胎儿瓣膜成熟和出生后的稳态。所提出的组合方法将加速诊断和控制瓣膜发育和钙化风险中临床可及的功能缺陷的分子策略的发展。

 DESCRIPTION (provided by applicant): Calcific aortic valve disease (CAVD) is an increasingly prevalent and life-threatening condition for which there are currently no clinically useful biological targets or therapeutic agents. Several compelling recent studies have identified common signaling pathways present in both aortic valve formation and calcific aortic stenosis, but our understanding of how these signals are integrated and coordinated at the cell and tissue level is very limited. The cellular mechanisms controlling elongation, condensation, and matrix stratification of the valve primordia are of highest clinical importance but are almost completely unknown. Further complicating matters is that these morphogenic and remodeling behaviors occur within a dynamic mechanical environment, the effects of which have been challenging to investigate due to a lack of research tools. Cadherin-11 is a cell-cell adhesion protein that regulates of collective mesenchymal cell migrations and their subsequent differentiation to osteogenic lineages, making it an attractive candidate for regulating valve formation and homeostasis. Cadherin-11 is strongly and specifically expressed in both the endocardium and mesenchyme of the endocardial cushions, but progressively downgrades in the mesenchyme as cushions elongate into valves. The preliminary data in this proposal demonstrates that deletion of cadherin-11 results in significant lethality during key valve remodeling periods. Conversely, valve specific overexpression of CDH11 is viable but with thickened aortic valves with regions of hypercellular interstitial aggregation and calcification typical of lesions seen in human CAVD. This proposal will test the hypothesis that a tight range of Cadherin-11 expression is essential for proper coordination of fetal valve cellularization, remodeling, and maturation for long-term homeostatic function. The first aim of the proposal will be to determine the mechanobiological role of cadherin- 11 in cellularization and remodeling of the embryonic aortic valve. Aim 2 will test how cadherin-11 regulates postnatal valve remodeling and calcification. Aim 3 of the proposal will test whether cadherin-11 rebalancing can rescue and/or prevent the development of aortic valve CHD and/or calcification. The results of this study will elaborate a novel tightly controlled and mechanically sensitive mechanism responsible for fetal valve maturation and postnatal homeostasis. The combinatorial approach presented will accelerate the development of molecular strategies that diagnose and control clinically accessible functional deficiencies in valve development and calcification risk.