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

• 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
• 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

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。 胚胎发生。主动脉瓣的模式是由基因控制的，其中瓣膜中的单个细胞 形成场根据位置和环境线索完善其命运和功能。遗传 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~2% 在美国普通人群中，BAV 是最常见的先天性心脏病。三者之二的融合 胚胎发生过程中出现小叶或缺少小叶会导致各种 BAV 亚型。出生后， 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 存在各种心脏并发症，这些并发症决定疾病的结局。与国际二尖瓣主动脉 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 预防。为此，我们生成了两种具有明显信号缺陷的 BAV 小鼠模型 异常传单。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——左右冠状动脉小叶的融合，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，模式缺陷与 VEC-VMC PDGFB 信号传导减弱有关。基于 根据这些发现，我们假设协调的 VEC-VMC 信号控制正常的主动脉瓣模式，并且 在受影响细胞的起源和位置的背景下，它们的破坏导致各种 BAV 亚型。我们将 在两个目标中检验这个假设。目标 1 计划揭示正常情况下协调的 VEC-VMC 信号网络 主动脉瓣模式并识别各种 BAV 亚型中被破坏的信号事件。目标2已设计 揭示 PDGF 信号在正常主动脉瓣模式中的功能，并以此为例 说明被破坏的信号事件如何改变细胞命运和功能，从而导致特定的 BAV。成功的 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。