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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

基本信息

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
项目类别：
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

项目摘要

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.