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 主动脉瘤疾病是美国的一个主要原因。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疗法。 AscAA 常见于先天性心脏病 (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 对 CHD 相关的 AscAA 知之甚少，但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，疾病进展和发生急性主动脉的风险 事件的预测很差，随后的临床指南也不充分。更好地了解主动脉 需要生物力学特性来弥合这一知识差距，确定疾病特定指标来指导 治疗，并产生更有效的治疗方法。 NOTCH1 的突变与 BAV 和 TOF 有关，我们之前描述了一种新的小鼠模型 其中Notch1单倍体不足足以引起AscAA。我们之前发布的数据表明 血管平滑肌细胞（SMC）前体在发育过程中的分化缺陷导致 Notch1+/- 成人主动脉中的异常 SMC 易患 AscAA，并暗示其胚胎学起源 CHD 相关主动脉病。我们假设 NOTCH1 信号传导的缺失会导致组织反应异常 血流动力学应力并导致壁刚度增加。这反过来又导致壁应变增加 主动脉夹层的风险。该项目的目标是进一步研究生物力学特性 CHD 相关的 AscAA 中的近端主动脉壁。 我们将通过 (1) 评估 Notch1 缺失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）评估上行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）评估近端内的生物力学特性 儿科 TOF 患者的升主动脉。成功完成这些目标将有助于弥合当前的困难 关于 CHD 相关 AscAA 疾病发病机制的知识差距，有助于改善临床 指导方针，并为新的治疗目标创造机会。