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Molecular signaling in aortic valve development and congenital aortic valve defect

主动脉瓣发育和先天性主动脉瓣缺陷的分子信号传导

基本信息

批准号：
10364556
负责人：
BIN ZHOU
金额：
$ 70.17万
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：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10364556
关键词：
3-Dimensional Affect Animal Model Aortic Aneurysm Aortic Valve Stenosis Apoptosis Birth Candidate Disease Gene Cardiac Cardiac Myocytes Cardiac Output Cell Lineage Cells Congenital Heart Defects Coronary Cues DNA Sequence Alteration Defect Development Developmental Process Disease Disease Outcome Dissection Embryo Embryonic Development Enhancers Epithelial Cells Event General Population Genes Genetic Heart Heart Valve Diseases Heterogeneity Human Immunofluorescence Immunologic In Situ Hybridization Individual Inherited International Intervention Knock-out Left Location Mediating Medicine Mesenchymal Modeling Molecular Mus Mutation NOTCH1 gene Operative Surgical Procedures PDGFB gene PDGFRA gene Pathogenesis Patients Pattern Phenotype Plant Roots Platelet-Derived Growth Factor Role SOX17 gene Severity of illness Signal Transduction Signaling Molecule Testing Therapeutic aortic valve aortic valve disorder autocrine base bicuspid aortic valve calcification clinical subtypes design disorder prevention effective therapy epithelial to mesenchymal transition experimental study gene network genetic signature human model in vivo insight mouse model mutant notch protein receptor response single-cell RNA sequencing spatiotemporal therapeutic target transcription factor

项目摘要

ABSTRACT The normal aortic valve is tricuspid with three leaflets derived from multiple cell lineages during embryogenesis. Aortic valve patterning is genetically controlled where individual cells in the valve- forming field refine their fates and functions in response to positional and environmental cues. Genetic mutations that alter cell-cell and cell-environmental signals can disrupt the developmental process, leading to anomalous aortic valve, for example, bicuspid aortic valve (BAV). Affecting ~2% of the general population in US, BAV is the most common congenital heart defect. Fusion of two of three leaflets or absence of one leaflet during embryogenesis results in various BAV subtypes. After birth, over half of BAV patients develop calcific aortic valve disease with no effective medicine, while BAV subtypes have varied cardiac complications, which decide the disease outcome. With the International Bicuspid Aortic Valve Consortium (BAVCon) being established to identify the genetic causes of BAV in humans, animal models of BAV are critically needed to elucidate morphogenic and cellular mechanisms of human BAV, as well as molecular signals that control aortic valve patterning in order to identify therapeutic targets for disease prevention. To this end, we have generated two mouse models of BAV with distinct signaling defects and anomalous leaflets. In the first model, knocking out notch receptor 1 (Notch1) in valve endocardial cells (VECs) recapitulates the most common human BAV subtype – fusion of left and right coronary leaflets, which are mainly derived from VECs by epithelial to mesenchymal transformation. This model also reveals that the NOTCH1- TNFa signaling from VECs controls apoptosis of valve mesenchymal cells (VMCs). In the second model, deleting SRY-box transcription factor 17 (Sox17) in VECs results in a rare but more severe type of BAV – absence of non-coronary leaflet, of which VMCs arise predominantly from the second heart field (SHF)-derived cardiomyocytes, and the patterning defect is associated with reduced VEC-VMC PDGFB signaling. Based on these findings, we hypothesize that coordinated VEC-VMC signals control normal aortic valve patterning and their disruption leads to various BAV subtypes, in the context of the origin and location of affected cells. We will test this hypothesis in two Aims. Aim 1 is planned to reveal coordinated VEC-VMC signal networks during normal aortic valve patterning and identify signaling events that are disrupted in various BAV subtypes. Aim 2 is designed to uncover the functions of PDGF signaling in normal aortic valve patterning as well as use it as an example to illustrate how a disrupted signaling event can alters cell fate and function, leading to a specific BAV. Successful accomplishment of these Aims will provide new insights into BAV pathogenesis, with a broad implication in congenital heart valve disease.

摘要