Adhesive signaling in aortic valve development and disease

主动脉瓣发育和疾病中的粘附信号传导

• 批准号: 9312882
• 负责人: Jonathan Talbot Butcher
• 金额: $ 38.77万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-17 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312882
• 关键词: Adhesions; Adhesives; Adult; Affect; Alpha Cell; Aortic Valve Stenosis; Behavior; Biological; Biological Assay; Cadherins; Calcified; Candidate Disease Gene; Cell-Cell Adhesion; Cells; Clinical; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Embryo; Endocardium; Endothelial Cells; Endothelium; Environment; Esthesia; Etiology; Event; Exhibits; Extracellular Matrix; Financial compensation; Genetic Models; Goals; Heart Valves; Homeostasis; Human; In Vitro; Integrins; Interactive Communication; Lesion; Life; Mechanical Stress; Mechanics; Mediating; Mesenchymal; Mesenchyme; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Mus; Pathogenesis; Pattern; Perinatal; Periodicity; Physical condensation; Play; Process; Production; Proteins; Repression; Research; Risk; Role; Signal Pathway; Signal Transduction; Stratification; Stretching; Survivors; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transgenic Mice; aortic valve; aortic valve disorder; base; beta catenin; cadherin-11; calcification; cell motility; cell type; clinical translation; clinically relevant; combinatorial; experimental study; fetal; in vivo; interstitial; interstitial cell; malformation; mechanotransduction; migration; novel; osteogenic; overexpression; postnatal; prevent; progenitor; programs; public health relevance; three dimensional cell culture; tool

 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.

 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，最近的几项引人注目的研究已经确定了主动脉中存在的常见信号传导途径。瓣膜形成和钙化性主动脉瓣狭窄，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。瓣膜原基具有最高的临床重要性，但几乎完全未知的是，这些形态发生和重塑行为发生在动态机械环境中，由于缺乏研究工具，其影响一直难以研究11。 Cadherin-11 是一种细胞间粘附蛋白，可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。在心内膜和心内膜垫的间充质中强烈且特异地表达，但随着垫伸长到瓣膜，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的缺失会导致关键瓣膜重塑期间的显着致死率。离线时，CDH11 的瓣膜特异性过表达是可行的，但主动脉瓣增厚，具有细胞间质聚集区域和典型病变的钙化该提案将检验以下假设：钙粘蛋白 11 表达的严格范围对于胎儿瓣膜细胞化、重塑和成熟的长期稳态功能至关重要。 cadherin-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 cadherin-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 cadherin-11 重新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负责胎儿瓣膜成熟和/或钙化的新型严格控制和机械敏感机制。所提出的组合方法将加速诊断和控制临床可及的瓣膜发育和钙化风险的功能缺陷的分子策略的开发。