Mechanisms of Coronary Ostium Formation and Coronary Artery Patterning

冠状动脉口形成和冠状动脉模式的机制

基本信息

批准号：
8580415
负责人：
BIN ZHOU
金额：
$ 39.75万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580415
关键词：
Ablation Address Anatomy Aorta Binding Biological Assay Blood Blood Circulation Blood Vessels Candidate Disease Gene Cardiac Myocytes Cells Clinical Color Coronary Coronary Circulation Coronary artery Data Defect Development Diffusion Embryo Embryonic Development Endocardium Endothelial Cells Endothelium Enhancers Etiology Genes Genetic Genetic Transcription Goals Growth Growth Factor Heart Hypoxia Immunofluorescence Immunologic Location Modeling Molecular Molecular Analysis Mus Muscle Cells Mutant Strains Mice Myocardial Myocardium Names Natural regeneration Nuclear Nutrient Outcome Oxygen Pathway interactions Pattern Pattern Formation Phase Phenotype Process Reporter Genes Role Signal Transduction Site Testing VEGFA gene Valsalva sinus Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Work base cell behavior heart circulation hypoxia inducible factor 1 mouse model nuclear factors of activated T-cells public health relevance receptor spatiotemporal stem transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): The broad and long-term goal of this project is to understand the patterning of coronary arteries and their underlying mechanisms. The coronary circulation starts when the passive diffusion of oxygen and nutrients is no longer sufficient for the heart growth and function. The coronary arteries must connect to the aorta through the coronary ostia, the openings at the aortic sinus, to receive the oxygenated blood and nutrients from systemic circulation. We have generated new genetic mouse models to study the developmental and molecular mechanisms of the coronary-aorta connection and coronary patterning. Preliminary results have shown that the myocardial vascular endothelial growth factor-a (Vegfa) is necessary for the connection to form. We have also found that the main receptor for Vegfa, Vegfr2, as well as transcription factor Nfatc1 are co- expressed in the aortic sinus endothelium. Additionally, the aortic sinus is surrounding by hypoxic cardiomyocytes that produce a high level of Vegfa. Building upon these findings, this project is to study in mice when and where the myocardial Vegfa is required for the coronary-aorta connection and whether its function is hypoxia-dependent. We will also address whether Vegfr2 and Nfatc1 function together to regulate the connection process. Specifically, we will genetically disrupt Vegfa, Vegfr2, or Nfatc1 in a spatiotemporal manner during late coronary artery development. Ablation of the hypoxic cardiomyocytes or their expression of Vegfa will establish the role of hypoxia in coronary artery patterning and ostium formation. Deletion of Vegfr2 and Nfatc1 in the endocardium of the aortic sinus will ascertain their roles and potential interactions in these processes. Morphologic, cellular, and molecular analysis of the developing coronary arteries and ostia in these mouse mutants will identify previously unknown developmental mechanisms and molecular interactions involved in late coronary artery development. The information will help understand the etiology of congenital coronary anomalies.

描述（由申请人提供）：该项目的广泛和长期目标是了解冠状动脉的模式及其潜在机制。当氧气和营养物质的被动扩散不再足以满足心脏的生长和功能时，冠状循环就开始了。冠状动脉必须通过冠状动脉口（主动脉窦的开口）连接到主动脉，以接收来自体循环的含氧血液和营养物质。我们已经建立了新的遗传小鼠模型来研究冠状动脉-主动脉连接和冠状动脉模式的发育和分子机制。初步结果表明，心肌血管内皮生长因子-a (Vegfa) 对于连接的形成是必需的。我们还发现Vegfa的主要受体Vegfr2以及转录因子Nfatc1在主动脉窦内皮细胞中共表达。此外，主动脉窦周围有缺氧的心肌细胞，可产生高水平的 Vegfa。基于这些发现，该项目旨在研究小鼠何时何地冠状动脉连接需要心肌 Vegfa，以及其功能是否依赖于缺氧。我们还将讨论 Vegfr2 和 Nfatc1 是否一起发挥作用来调节连接过程。具体来说，我们将在冠状动脉发育晚期以时空方式从基因上破坏 Vegfa、Vegfr2 或 Nfatc1。消融缺氧心肌细胞或其 Vegfa 表达将确定缺氧在冠状动脉模式和开口形成中的作用。主动脉窦心内膜中 Vegfr2 和 Nfatc1 的缺失将确定它们在这些过程中的作用和潜在的相互作用。对这些小鼠突变体中正在发育的冠状动脉和窦口进行形态学、细胞和分子分析，将鉴定出先前未知的发育机制和参与晚期冠状动脉发育的分子相互作用。这些信息将有助于了解先天性冠状动脉异常的病因。