ROS Mechanisms in BAV Aortopathy

BAV 主动脉病中的 ROS 机制

• 批准号: 10733581
• 负责人: Thomas Gillette Gleason
• 金额: $ 66.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733581
• 关键词: ROS; Mechanisms; BAV; Aortopathy

PROJECT SUMMARY Ascending aortic aneurysmal disease is a major worldwide health problem. Bicuspid aortic valve (BAV)- associated aortopathy represents the largest subset of affected patients and this congenital anomaly is present in 1-2% of the general population. Current aortic diameter-based guidelines for surgical intervention stem from a non-controlled extrapolation of natural history data that does not reflect patient-specific aortic catastrophe risk rendering under-treatment in some patients and over-treatment in others. This is largely because there is an incomplete understanding of what biological and biomechanical features are unique to BAV-associated aortopathy or other degenerative aneurysms and how these insults potentiate aortic dissection. During the prior funding period, we uncovered several cellular, tissue architectural, and biomechanical-based features distinguishing BAV-associated aortopathy from that of degenerative aneurysms. We discovered that elevated production of superoxide anion by medial smooth muscle cells, increased oxidative stress-induced cellular damages, and a biomechanical strength profile coupled with an anisotrophic collagen and elastin microarchitecture uniquely define the tissue microenvironment of the BAV aorta. In the next phase of the project, we will elucidate how an interplay of mechanical and oxidative stress mediates ECM remodeling, determine where hypoxia comes into play, and how clinical imaging-derived metrics correspond to cellular and tissue aberrations in the BAV aorta. In a two-aim approach, we will test the central hypothesis that mechanical forces- and local hypoxia-induced oxidative stress invokes differential ECM remodeling in BAV and TAV patients, and these insults can be correlated to patient-specific aortic wall indices that can be imaged, bundled and used to predict disease progression and/or aortic catastrophe. Aim 1's approach will employ our established patient-specific 3D culture models to determine how mechanical stretch and low oxygen tension impact antioxidant response, free radical production, cellular oxidative damages, and influence ECM production, microarchitecture and degradation in BAV aorta-derived smooth muscle cells. In Aim 2, quantification of local hypoxic effects, measures of oxidative cellular damages, ECM microarchitecture, and biochemical ECM composition will be regionally compared and then correlated with patient-specific wall shear stress measurements from 4D flow MRI, aortic wall morphometrics from dynamic ECG-gated CTA, and distensibility metrics from echocardiography to develop a workable patient-specific multi-parameter imaging- based paradigm. Completion of this project phase will generate an aortic bio-map that profiles mechanical and oxidative stress-mediated ECM remodeling in BAV-associated aortopathy and will identify what in vivo bio- imaging endpoints correlate with these tissue insults. A perceived deliverable is a set of building blocks for a workable multi-parameter computational model whose main output will be a patient specific aortic integrity score that more accurately identifies dissection risk for a given patient. This work will also reveal new opportunities for the implementation of PET-based probes to non-invasively detect local aortic vulnerability and identify novel targets for medical therapeutic intervention.

项目摘要 升主动脉粥样硬化性疾病是一个世界性的重大健康问题。二叶式主动脉瓣（BAV）- 相关的脊椎病代表了受累患者的最大亚群， 占总人口的1-2%。目前基于主动脉直径的外科干预指南源于 自然史数据的非对照外推，不反映患者特异性主动脉灾难 可能导致一些患者治疗不足，另一些患者治疗过度。这主要是因为， 对BAV相关的生物学和生物力学特征的不完全理解 动脉瘤或其他退行性动脉瘤以及这些损伤如何加重主动脉夹层。期间 在前一个资助期，我们发现了几个细胞，组织结构和生物力学为基础的功能 区分BAV相关动脉瘤病与退行性动脉瘤。我们发现， 中膜平滑肌细胞产生超氧阴离子，增加氧化应激诱导的细胞 损伤，以及生物力学强度曲线与各向异性胶原蛋白和弹性蛋白相结合 微结构独特地限定了BAV主动脉的组织微环境。下一阶段 项目，我们将阐明如何相互作用的机械和氧化应激介导ECM重塑， 确定缺氧在哪里起作用，以及临床成像衍生的指标如何对应于细胞和 BAV主动脉的组织畸变在一个双目标的方法，我们将测试的中心假设，机械 力和局部缺氧诱导的氧化应激引起BAV和TAV的不同ECM重塑 患者，并且这些损伤可以与可以成像、捆绑 并用于预测疾病进展和/或主动脉灾难。Aim 1的方法将采用我们的 建立了患者特定的3D培养模型，以确定机械拉伸和低氧张力 影响抗氧化反应、自由基产生、细胞氧化损伤和影响ECM 在BAV血管衍生的平滑肌细胞中的产生、微结构和降解。在目标2中， 局部缺氧效应的定量，氧化性细胞损伤的测量，ECM微结构，和 生化ECM成分将进行区域比较，然后与患者特异性壁剪切力相关 来自4D Flow MRI的应力测量、来自动态ECG门控CTA的主动脉壁形态测量，以及 超声心动图的扩张性指标，以开发可行的患者特异性多参数成像- 基于范式。本项目阶段的完成将生成主动脉生物图谱， 氧化应激介导的细胞外基质重塑在BAV相关的动脉粥样硬化病，并将确定在体内生物- 成像终点与这些组织损伤相关。可感知的可交付成果是一组构建块， 可行的多参数计算模型，其主要输出将是患者特定的主动脉完整性 更准确地识别给定患者的夹层风险的评分。这项工作还将揭示新的 实施基于PET的探头以非侵入性检测局部主动脉易损性的机会， 鉴定用于医学治疗干预的新靶点。