Embryologic Origins of Aortopathy: Biomechanical Characterization of Aortic Aneurysms in the NOTCH1 Mutant Model

项目摘要 在美国，主动脉瘤疾病是导致死亡的主要原因。升主动脉瘤(AscAA)是 与主动脉夹层和破裂相关，由于缺乏 症状和有限的非手术治疗。AscAA常伴有先天性心脏病(CHD)， 特别是二尖瓣主动脉瓣(BAV)和法洛四联症(TOF)。然而，其分子机制 与冠心病相关的AscAA知之甚少，而且越来越多的证据表明，动脉瘤的机制 形成和发展是不同的。因此，疾病进展和发生急性主动脉病变的风险 事件的预测很差，后续的临床指南也不充分。对主动脉有更好的了解 需要生物力学特性来弥合这一知识鸿沟，确定疾病特异性指标来指导 治疗，并产生更有效的治疗方法。 NOTCH1的突变与BAV和TOF有关，我们之前在 哪种Notch1单倍体不足足以导致AscAA。我们之前公布的数据表明 血管平滑肌细胞前体细胞在发育过程中的分化缺陷有助于 Notch1+/-成人主动脉中异常的SMC易患AscAA并提示其胚胎起源 冠心病相关的大动脉病变。我们假设NOTCH1信号的丢失会导致组织的异常反应 导致血流动力学应力增加，导致室壁僵硬增加。这进而导致墙体应变的增加和 主动脉夹层的风险。本项目的目标是进一步研究人工关节的生物力学特性。 冠心病相关腹主动脉曲张的近端主动脉壁。 我们将通过(1)评估Notch1缺失对血管内皮细胞表型的影响来验证我们的假设。 对损伤的反应，(2)评估升支内平滑肌细胞的生物力学特性 NOTCH1单倍体不足小鼠的主动脉，以及(3)评估近端的生物力学特性 儿童TOF患者的升主动脉。这些目标的成功实现将有助于弥合当前的 对冠心病相关腹主动脉疾病发病机制的认识差距，有助于改善临床 指南，并为新的治疗靶点创造机会。

PROJECT ABSTRACT Aortic aneurysmal disease is a leading causes of death in the US. Ascending aortic aneurysms (AscAA) are associated with aortic dissection and rupture causing significant morbidity and mortality due to a lack of symptoms and limited non-surgical therapies. AscAA are frequently found with congenital heart defects (CHD), specifically bicuspid aortic valve (BAV) and tetralogy of Fallot (TOF). However, the molecular mechanism of CHD-associated AscAA is poorly understood and there is growing evidence that the mechanism of aneurysm formation and progression is heterogeneous. As such, disease progression and risk of developing an acute aortic event is poorly predicted and subsequent clinical guidelines are inadequate. A better understanding of the aortic biomechanical properties is needed to bridge this knowledge gap, identify disease-specific indicators to guide therapy, and produce more effective therapeutics. Mutations in NOTCH1 have been linked to BAV and TOF and we previously described a novel mouse model in which Notch1 haploinsufficiency is sufficient to cause AscAA. Our previously published data suggests that differentiation defects of vascular smooth muscle cell (SMC)-precursors during development contribute to abnormal SMCs in the Notch1+/- adult aorta predisposing to AscAA and implicating an embryologic origin of CHD-associate aortopathy. We hypothesize that loss of NOTCH1 signaling leads to an abnormal tissue response to hemodynamic stress and results in increased wall stiffness. This in turn leads to an increase in wall strain and risk of aortic dissection. The goal of this project is to further investigate the biomechanical properties of the proximal aortic wall in CHD-associated AscAA. We will test our hypothesis by (1) assessing the effects of loss of Notch1 on smooth muscle cell phenotype in response to injury, (2) assessing the biomechanical properties of the smooth muscle cells within the ascending aortas of NOTCH1 haploinsufficent mice, and(3) assessing the biomechanical properties within the proximal ascending aorta of pediatric TOF patients. Successful completion of these aims will help to bridge the current knowledge gap regarding pathogenesis of CHD-associated AscAA disease, assist in improving clinical guidelines, and create opportunities for new therapeutic targets.