Adhesive signaling in aortic valve development and disease

 说明(申请人提供)：钙化性主动脉瓣病(CAVD)是一种日益流行的威胁生命的疾病，目前还没有临床上有用的生物靶点或治疗剂。最近一些引人注目的研究已经确定了在主动脉瓣形成和钙化性主动脉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了解非常有限。控制瓣膜原基延长、凝结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。更复杂的是，这些形态形成和重塑行为发生在动态的机械环境中，由于缺乏研究工具，其影响一直难以研究。钙粘蛋白-11是一种细胞-细胞黏附蛋白，调节间充质细胞的集体迁移和随后向成骨细胞的分化，使其成为调节瓣膜形成和动态平衡的候选分子。钙粘蛋白-11在心内膜和心内膜垫的间质中都有强烈和特异的表达，但随着心内膜垫延伸到瓣膜中，在间质中的表达逐渐减弱。这项建议中的初步数据表明，在关键的瓣膜重塑时期，钙粘素-11的缺失会导致显著的致命性。相反，CDH11的瓣膜特异性过表达是可行的，但伴有增厚的主动脉瓣，有高细胞间质聚集和钙化区域，这是人类CAVD中常见的病变。这一建议将检验一种假设，即小范围的钙粘连蛋白-11的表达对于胎儿瓣膜细胞化、重塑和长期内稳功能的成熟是必要的。该提案的第一个目标将是确定钙粘蛋白-11在胚胎主动脉瓣细胞化和重塑中的机械生物学作用。目的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/或防止主动脉瓣先天性心脏病和/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体内平衡。提出的组合方法将加速分子策略的发展，以诊断和控制临床上可获得的瓣膜发育和钙化风险的功能缺陷。

 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.