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

主动脉病的胚胎学起源：NOTCH1 突变模型中主动脉瘤的生物力学特征

• 批准号: 10563119
• 负责人: Ruth Ackah
• 金额: $ 6.07万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10563119
• 关键词: Acute; Adolescent; Adult; Aneurysm; Aorta; Aortic Aneurysm; Aortic Segment; Area; Biomechanics; Cardiac; Cardiovascular system; Cause of Death; Cells; Child; Childhood; Clinical; Complication; Congenital Heart Defects; Consensus; Data; Defect; Development; Disease; Disease Progression; Dissection; Distal; Event; Genes; Goals; Guidelines; Heart; Heterogeneity; Human; Imaging technology; Intervention; Investigation; Knowledge; Lead; Link; Measurement; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle satellite cell; Mutation; Myoblasts; NOTCH1 gene; Nature; Neural Crest; Pathogenesis; Pathway interactions; Patient Care; Patients; Phenotype; Physiologic pulse; Plant Roots; Population; Property; Publishing; Regulator Genes; Risk; Rupture; Signal Transduction; Smooth Muscle Myocytes; Stress; Symptoms; Testing; Tetralogy of Fallot; Therapeutic; Thoracic aorta; Tissues; United States; Vascular Smooth Muscle; Work; ascending aorta; bicuspid aortic valve; biomechanical test; cardiac magnetic resonance imaging; clinical predictors; congenital heart disorder; disorder risk; hemodynamics; improved; improved outcome; mortality; mouse model; mutant; new therapeutic target; novel; response; response to injury; risk stratification; stem cells; therapeutically effective; two-dimensional

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.

项目摘要 主动脉瘤性是美国死亡的主要原因。上升主动脉瘤（ASCAA）是 与主动脉夹层和破裂相关，导致由于缺乏 症状和有限的非手术疗法。经常发现先天性心脏缺陷（CHD），ASCAA， 特异性双质主动脉瓣（BAV）和四曲（ToF）（TOF）。但是， 与CHD相关的ASCAA知之甚少，并且有越来越多的证据表明动脉瘤的机制 形成和进展是异质的。因此，疾病的进展和发展急性主动脉的风险 事件的预测很差，随后的临床指南不足。更好地理解主动脉 需要生物力学特性来弥合此知识差距，确定特定疾病的指标以指导 治疗并产生更有效的治疗疗法。 Notch1中的突变已与BAV和TOF相关联，我们先前描述了一种新的小鼠模型 哪种notch1单倍度不足足以引起ASCAA。我们先前发布的数据表明 发育过程中血管平滑肌细胞（SMC）的分化缺陷有助于 Notch1 +/-成人主动脉中的异常SMC倾向于ASCAA，并暗示了胚胎的起源 CHD缔解主动脉疾病。我们假设Notch1信号传导的丢失导致组织异常反应 血液动力学压力并导致壁刚度增加。这反过 主动脉夹层的风险。该项目的目的是进一步研究 与CHD相关的ASCAA中的近端主动脉壁。 我们将通过（1）评估Notch1对平滑肌细胞表型的影响来检验我们的假设 对损伤的反应，（2）评估上升中平滑肌细胞的生物力学特性 Notch1单倍弹性小鼠的主动脉，（3）评估近端内的生物力学特性 小儿TOF患者的主动脉升高。这些目标的成功完成将有助于弥合当前 有关冠心病相关的ASCAA疾病发病机理的知识差距，有助于改善临床 指南，并为新的治疗靶标创造机会。