Endothelial Cell Growth and Differentiation in Semilunar Heart Valves

半月形心脏瓣膜内皮细胞的生长和分化

• 批准号: 7214098
• 负责人: Joyce E. Bischoff
• 金额: $ 34.56万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214098
• 关键词: Adult; Affect; Birth; Blood flow; Cell Proliferation; Congenital Abnormality; Congenital Heart Defects; DNA Microarray Chip; DNA Microarray format; Data; Defect; Development; Developmental Process; Embryo; Endothelial Cells; Endothelium; Event; Exhibits; Gel; Gene Expression; Gene Targeting; Genes; Heart; Heart Valve Diseases; Heart Valves; Human; Infant; Life; Link; Lung; Mediating; Mesenchymal; Modeling; Molecular; Mus; Natural regeneration; Nuclear Translocation; Oxygen; Pathway interactions; Patients; Population; Process; Property; Pulmonary valve structure; Regulation; Role; Signal Pathway; Signal Transduction; Testing; Tissue Engineering; Tissues; Transforming Growth Factor beta; Up-Regulation; Vascular Endothelial Growth Factors; aortic valve; base; bone morphogenetic protein 2; cell growth; heart function; improved; insight; migration; prevent; repaired; tandem mass spectrometry; tool; transcription factor; transdifferentiation

DESCRIPTION (provided by applicant): Properly formed heart valve leaflets are essential to achieve unidirectional blood flow and thus, are critical for life. The delicate leaflets open and close with each heart beat, promoting optimal heart function by preventing regurgitation and thus, oxygen delivery to tissues throughout the body. Congenital heart defects, many of which affect the heart valves, occur in about 1 in 100 infants. Some congenital valve defects are life threatening from the moment of birth; others are less problematic, but eventually valve replacement becomes necessary in adult life. Despite the critical role of the valves in heart function, relatively little is known about the development of the valves and even less about the cellular and molecular processes that sustain valve function through adult life. We have shown that endothelial cells from adult pulmonary and aortic valve leaflets exhibit valve specific properties that are reminiscent of critical steps in valvulogenesis, indicating that endothelial cells from adult leaflets retain the ability to recapitulate embryonic developmental processes. We have shown that in human valvular endothelial cells, activation and nuclear translocation of the transcription factor NFATc1 is required for VEGF-induced proliferation and migration, we have also shown that clonal populations of adult valvular endothelial cells can be induced to undergo an endothelial to mesenchymal transdifferentiation (EMT), a critical event in formation of valve leaflets from the endocardial cushions. The valvular endothelial cell culture models we have established provide powerful tools for identifying genes that control endothelial proliferation and differentiation and for understanding the interplay between proliferation and differentiation in cardiac valves. Three specific aims will be pursued. The first will be to identify and functionally characterize targets of the VEGF/NFATc1 signaling pathway in valve endothelium. The second will be to identify and functionally characterize genes involved in TGF-beta mediated EMT. The third aim will be to examine the cross-regulation between proliferation and differentiation in cardiac valve endothelial cells. Based on new preliminary data, we hypothesize the bone morphogenetic protein-2 (BMP-2) links these two pathways. Aim 3 has been expanded in this revised application to specifically test the role of BMP-2 in proliferation, migration and EMT in cardiac valve endothelium. The studies proposed here will provide insights on 1) normal functions and capabilities of valvular endothelium, 2) heart valve diseases and potential mechanisms for repair, and 3) strategies to create improved valve replacements for patients suffering from valve-specific defects.

描述（由申请人提供）：正确形成的心脏瓣膜小叶对于实现单向血流至关重要，因此对生命至关重要。细腻的小叶在每次心脏跳动时都打开和闭合，通过防止反流以及氧气递送到整个身体的组织来促进最佳心脏功能。先天性心脏缺陷（其中许多都会影响心脏瓣膜）发生在100名婴儿中大约1个。一些先天性瓣膜缺陷从出生开始就威胁生命。其他人的问题较小，但最终在成人生活中需要更换阀门。尽管瓣膜在心脏功能中的重要作用至关重要，但对瓣膜的发育的了解相对较少，甚至对通过成人寿命维持瓣膜功能的细胞和分子过程的了解却更少。我们已经表明，来自成年肺部和主动脉瓣膜的内皮细胞表现出特定瓣膜特性，这些特性让人联想到瓣膜发生的关键步骤，表明来自成年小叶的内皮细胞保留了概括胚胎发育过程的能力。我们已经表明，在人瓣膜内皮细胞中，转录因子NFATC1的激活和核易位是VEGF诱导的增殖和迁移所必需的，我们还表明，可以诱导成人瓣膜内皮细胞的克隆种群，以使其对中等层状的内皮构成（Emt）的杂物（EMT），并在范围内进行了范围的事件。我们已经建立的瓣膜内皮细胞培养模型为识别控制内皮增殖和分化的基因提供了强大的工具，并了解心脏瓣膜中增殖与分化之间的相互作用。将追求三个具体目标。第一个是识别并在功能上表征阀内皮中VEGF/NFATC1信号通路的目标。第二个将是识别并在功能上表征与TGF-β介导的EMT有关的基因。第三个目的是检查心脏瓣膜内皮细胞增殖与分化之间的交叉调节。根据新的初步数据，我们假设骨形态发生蛋白-2（BMP-2）将这两种途径联系起来。 AIM 3在此修订后的应用中已扩展，以专门检验BMP-2在心脏瓣膜内皮中增殖，迁移和EMT中的作用。这里提出的研究将提供有关1）瓣膜内皮的正常功能和功能的见解，2）心脏瓣膜疾病和维修的潜在机制，以及3）为患有瓣膜特异性缺陷的患者提供改进的瓣膜更换的策略。