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

项目摘要 主动脉瘤疾病是美国的主要死亡原因。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经常与先天性心脏病（CHD）一起发现， 特别是二叶主动脉瓣（BAV）和法洛四联症（TOF）。然而， CHD相关的AscAA知之甚少，越来越多的证据表明动脉瘤的机制 形成和发展是异质的。因此，疾病进展和发生急性主动脉瘤的风险 事件预测不佳，后续临床指南不充分。更好地了解主动脉 生物力学特性需要弥合这一知识差距，确定疾病特异性指标，以指导 治疗，并产生更有效的治疗方法。 NOTCH 1的突变与BAV和TOF有关，我们先前描述了一种新的小鼠模型， Notch 1单倍不足足以导致AscAA。我们之前公布的数据表明， 血管平滑肌细胞（SMC）-前体细胞在发育过程中的分化缺陷有助于 Notch 1 +/-成人主动脉中的异常平滑肌细胞易患AscAA，并提示 CHD相关性腰椎病。我们假设NOTCH 1信号的缺失导致异常的组织反应 血液动力学应力，并导致增加的壁刚度。这又导致壁应变的增加， 主动脉夹层的风险。本项目的目标是进一步研究生物力学性能的 CHD相关AscAA的近端主动脉壁。 我们将通过以下方法检验我们的假设：（1）评估Notch 1缺失对平滑肌细胞表型的影响， 对损伤的反应，（2）评估升支内平滑肌细胞的生物力学特性， NOTCH 1单倍体不足小鼠的骨密度，以及（3）评估近端骨内的生物力学特性。 小儿TOF患者的升主动脉。成功地完成这些目标将有助于弥合目前的差距， 关于CHD相关AscAA疾病发病机制的知识缺口，有助于改善临床 指导方针，并为新的治疗目标创造机会。

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.