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：
10544023
负责人：
BIN ZHOU
金额：
$ 72.18万
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 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544023
关键词：
3-Dimensional Affect Animal Model Aorta 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 Platelet-Derived Growth Factor Role SOX17 gene Severity of illness Signal Transduction Signaling Molecule Testing Therapeutic aortic valve aortic valve disorder autocrine bicuspid aortic valve 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.

抽象的正常的主动脉瓣是三尖瓣，具有来自多个细胞谱系的三个小叶。主动脉瓣膜的形成是由基因控制的，其中瓣膜中的单个细胞形成场根据位置和环境遗传线索完善其命运和功能。改变细胞间和细胞环境信号的突变会破坏发育过程，导致主动脉瓣异常，例如二叶式主动脉瓣 (BAV)，影响约 2% 的患者。在美国普通人群中，BAV 是三种先天性心脏病中最常见的两种融合。胚胎发生过程中出现小叶或缺乏小叶会导致出生后产生各种 BAV 亚型。超过一半的 BAV 患者出现钙化性主动脉瓣疾病且无有效药物，而 BAV 亚型有不同的心脏并发症，这决定了国际二尖瓣主动脉疾病的结果。 Valve Consortium (BAVCon) 的成立旨在确定人类和动物模型中 BAV 的遗传原因阐明人类 BAV 的形态发生和细胞机制至关重要控制主动脉瓣模式的分子信号，以确定疾病的治疗靶点为此，我们构建了两种具有不同信号缺陷的 BAV 小鼠模型。在第一个模型中，敲除瓣膜心内膜细胞 (VEC) 中的 Notch 受体 1 (Notch1)。概括了最常见的人类 BAV 亚型——左右冠状动脉瓣叶融合，主要是通过上皮细胞向间质细胞转化衍生自 VEC。该模型还揭示了 NOTCH1-。来自 VEC 的 TNFa 信号传导控制瓣膜间充质细胞 (VMC) 的凋亡。在第二个模型中，删除。 VEC 中的 SRY 盒转录因子 17 (Sox17) 会导致一种罕见但更严重的 BAV 类型——缺乏非冠状动脉小叶，其中VMC主要来自第二心脏区域（SHF）心肌细胞的模式缺陷与 VEC-VMC PDGFB 信号传导减少有关。这些发现，我们追求协调的 VEC-VMC 信号控制正常的主动脉瓣模式和根据受影响细胞的起源和位置，它们的破坏会导致各种 BAV 亚型。在两个目标中测试这一假设目标 1 计划揭示正常情况下协调的 VEC-VMC 信号网络。 Aim 2 旨在分析主动脉瓣模式并识别各种 BAV 亚型中被破坏的信号事件。揭示 PDGF 信号在正常主动脉瓣模式中的功能，并以此为例说明中断的信号事件如何改变细胞命运和功能，从而导致特定的 BAV 成功。这些目标的实现将为 BAV 发病机制提供新的见解，具有广泛的意义先天性心脏瓣膜病。