Molecular Mechanisms of Aortic Valve Formation

主动脉瓣形成的分子机制

基本信息

批准号：
8915429
负责人：
Vidu Garg
金额：
$ 37.38万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
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：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915429
关键词：
Address Age Alleles Backcrossings Bicuspid Cardiac Cause of Death Cell Lineage Cells Complex Congenital Abnormality Congenital Heart Defects Cyclic GMP Data Defect Development Disease Disease model Embryo Endothelial Cells Endothelium Epigenetic Process Family Study Functional disorder Gene Expression Gene Targeting Genetic Predisposition to Disease Heart Heart Valve Diseases Heart Valves Heterozygote Histologic Human Incidence Investigation Knowledge Lead Maps Mesenchymal Mesenchyme Modeling Molecular Molecular Abnormality Molecular Analysis Morbidity - disease rate Morphogenesis Mus Mutant Strains Mice Mutation Myocardial NOTCH1 gene Neural Crest Cell Nitric Oxide Pathogenesis Pathway interactions Phenotype Population Prevalence Prevention strategy Public Health Publications Publishing Pulmonary valve structure Reporting Research Signal Transduction Staging Stenosis Surgical Valves Testing Transgenic Mice aortic valve aortic valve disorder base bicuspid aortic valve clinically relevant congenital heart disorder human NOS3 protein infant death malformation mouse model mutant new therapeutic target notch protein novel prevent public health relevance semilunar valve treatment strategy valve replacement

项目摘要

DESCRIPTION (provided by applicant): Congenital heart disease is the most common type of birth defect and is the leading non-infectious cause of death in the first year of life. Malformations of the aortic valves are arguably the most common type of cardiac malformation as bicuspid aortic valve alone has an estimated prevalence of 1-2% in the population. The mechanisms underlying the development of aortic valve abnormalities are not well understood. We were the first to report that heterozygous mutations in NOTCH1 were associated with bicuspid aortic valve in humans but there remains a major void in our understanding of the mechanisms by which aortic valve malformations occur. We have generated a new mouse model of highly penetrant aortic valve malformations (bicuspid aortic valve) using Notch1 heterozygote mice backcrossed into a Nos3 (endothelial nitric oxide synthase)-null background. These mice display a near 100% incidence of aortic valve abnormalities including thickened, bicuspid and dysfunctional aortic valves. Our preliminary studies suggest that Nos3 genetically interacts with Notch1 in the valve endothelium to cause valve stenosis. Additional studies suggest that loss of Nos3 inhibits Notch1 signaling in endothelial cells to cause valve defects by an epigenetic mechanism. The overall hypothesis is that deficiency of Notch1 in endothelial cell lineages leads to BAV by disrupting the remodeling of developing aortic valve cushion mesenchyme. In this proposal, we will elucidate the cellular and molecular abnormalities in this clinically relevant model of aortic valve malformations. The specific aims of the proposal are: Specific Aim 1. To define the cellular and molecular mechanisms underlying the development of bicuspid aortic valve. Specific Aim 2. To determine the cell lineage requirement for Notch1 signaling for normal aortic valve morphogenesis. Specific Aim 3. To determine the mechanisms by which nitric oxide regulates Notch1 in the remodeling aortic valve.

描述（由适用提供）：先天性心脏病是最常见的先天缺陷类型，是生命第一年的主要非感染死亡原因。主动脉瓣的畸形可以说是最常见的心脏畸形类型，因为单独的双质主动脉瓣在人群中估计患病率为1-2％。主动脉瓣异常发展的基础机制尚不清楚。我们是第一个报告说，Notch1中的杂合突变与人类的双质主动脉瓣有关，但在我们对主动脉瓣畸形发生的机制的理解中仍然存在主要空隙。我们已经使用Notch1杂合子小鼠生成了一个高度渗透主动脉瓣畸形（双质主动脉瓣）的新小鼠模型，该模型被串入NOS3（内皮一氧化氮合酶） - null背景。这些小鼠的主动脉瓣异常的发生率接近100％，包括增厚，双刺和功能障碍主动脉瓣。我们的初步研究表明，NOS3一般与阀门植物中的Notch1相互作用，以引起瓣膜狭窄。进一步的研究表明，NOS3的丢失会抑制森林细胞中的Notch1信号传导，从而通过表观遗传机制引起瓣膜缺陷。总体上的假设是，洞穴细胞谱系中Notch1的缺乏通过破坏发展主动脉瓣垫Messyme的重塑而导致BAV。在此提案中，我们将阐明这种临床相关的主动脉瓣畸形模型中的细胞和分子异常。该提案的具体目的是：特定目的1。定义双质主动脉瓣发展的细胞和分子机制。具体目标2。确定正常主动脉瓣形态发生的NOTCH1信号的细胞谱系要求。特定目的3。确定一氧化氮调节重塑主动脉瓣中Notch1的机制。