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: 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
• 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

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的，三个小叶在多个细胞谱系中得出 胚胎发生。主动脉瓣模式受遗传控制，其中瓣膜中的单个细胞 形成领域根据位置和环境线索的响应来完善其命运和功能。遗传 改变细胞细胞和细胞环境信号的突变会破坏发育过程， 导致异常主动脉瓣，例如双质主动脉瓣（BAV）。影响约2％ 在美国，BAV是最常见的先天性心脏缺陷。融合三个中的两个 在胚胎发生过程中，小叶或没有一个小叶会导致各种BAV亚型。出生后， 超过一半的BAV患者患有钙化主动脉瓣疾病，没有有效的药物，而BAV亚型 心脏并发症多样，决定疾病结果。与国际双休uspid主动脉 建立阀财团（BAVCON）以识别人类BAV的遗传原因，动物模型 BAV的迫切需要阐明人类BAV的形态学和细胞机制，以及 控制主动脉瓣模式的分子信号，以鉴定疾病的治疗靶标 预防。为此，我们生成了两个具有不同信号缺陷的BAV的鼠标模型，并且 异常的传单。在第一个模型中，在瓣膜内膜细胞中敲出Notch受体1（Notch1）（VEC） 概括了最常见的人类BAV亚型 - 左右冠状动脉传单的融合，主要是 通过上皮到间充质转化源自VEC。该模型还表明Notch1- VECS的TNFA信号控制瓣膜间充质细胞的凋亡（VMC）。在第二个模型中，删除 VEC中的Sry-box转录因子17（Sox17）导致罕见但更严重的BAV - 不存在 非冠状小叶，其中VMC主要来自第二个心脏场（SHF）衍生 心肌细胞和模式缺陷与VEC-VMC PDGFB信号降低有关。基于 这些发现，我们假设协调的VEC-VMC信号控制着正常主动脉瓣形成和 在受影响的细胞的起源和位置的背景下，它们的破坏会导致各种BAV亚型。我们将 在两个目标中检验该假设。 AIM 1计划在正常情况下揭示协调的VEC-VMC信号网络 主动脉瓣模式并识别各种BAV亚型中破坏的信号事件。 AIM 2是设计的 揭示正常主动脉瓣图案中PDGF信号传导的功能，并以此为例 说明了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发病机理提供新的见解，并具有广泛的含义 先天性心脏瓣膜疾病。