ROS mechanisms in BAV aortopathy

BAV 主动脉病中的 ROS 机制

• 批准号: 10439298
• 负责人: Thomas Gillette Gleason
• 金额: $ 69.68万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 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/10439298
• 关键词: 4D MRI; Acute; Affect; Aneurysm; Angiography; Antioxidants; Aorta; Architecture; Biochemical; Biological; Biology; Biomechanics; Caliber; Cardiac Surgery procedures; Caring; Cause of Death; Clinical; Clinical Trials; Collagen; Complex; Computer Models; Coupled; Data; Diagnostic; Dimensions; Disease; Disease Progression; Dissection; Early Diagnosis; Early Intervention; Echocardiography; Elastin; Electrocardiogram; Etiology; Event; Exposure to; Extracellular Matrix; Free Radicals; Funding; General Population; Goals; Guidelines; Health; Hypoxia; Image; Intervention; Maps; Measurement; Measures; Mechanical Stress; Mechanics; Medial; Mediating; Medical; Modeling; Molecular; Natural History; Operative Surgical Procedures; Output; Oxidative Stress; Oxygen; Patient Care; Patient risk; Patients; Phase; Pimonidazole; Play; Positron-Emission Tomography; Predisposition; Preventive; Production; Publishing; Risk; Smooth Muscle Myocytes; Specimen; Stress; Stretching; Superoxides; System; Testing; Therapeutic Intervention; Thoracic Aortic Aneurysm; Tissues; United States; United States National Institutes of Health; Work; X-Ray Computed Tomography; adjudicate; adjudication; aortic valve; base; bicuspid aortic valve; bioimaging; cell injury; clinical imaging; cohort; congenital anomaly; design; efficacy testing; in vivo; indexing; mechanical force; mechanical properties; new therapeutic target; novel; novel diagnostics; overtreatment; oxidative damage; patient population; preservation; prevent; response; scaffold; shear stress; stem; stressor; surgical risk; three dimensional cell culture; tool; uptake

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.

项目概要 升主动脉瘤疾病是一个重大的全球健康问题。二叶式主动脉瓣 (BAV)- 相关主动脉病代表了受影响患者的最大子集，并且存在这种先天性异常 占总人口的 1-2%。目前基于主动脉直径的手术干预指南源于 自然历史数据的非受控外推，不反映患者特定的主动脉灾难 存在导致某些患者治疗不足和其他患者过度治疗的风险。这很大程度上是因为有 对 BAV 相关的独特生物学和生物力学特征的了解不完全 主动脉病或其他退行性动脉瘤以及这些损伤如何加剧主动脉夹层。期间 在之前的资助期间，我们发现了一些基于细胞、组织结构和生物力学的特征 区分 BAV 相关主动脉病和退行性动脉瘤。我们发现升高 内侧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、生物力学强度分布以及各向异性胶原蛋白和弹性蛋白 微结构独特地定义了 BAV 主动脉的组织微环境。在下一阶段 项目中，我们将阐明机械应激和氧化应激的相互作用如何介导 ECM 重塑， 确定缺氧在哪里发挥作用，以及临床成像衍生的指标如何与细胞和细胞相对应 BAV 主动脉的组织畸变。在双目标方法中，我们将测试机械的中心假设 力和局部缺氧诱导的氧化应激引起 BAV 和 TAV 中不同的 ECM 重塑 患者，这些损伤可以与患者特定的主动脉壁指数相关，这些指数可以被成像、捆绑 并用于预测疾病进展和/或主动脉灾难。目标 1 的方法将采用我们的 建立了患者特异性 3D 培养模型，以确定机械拉伸和低氧张力如何 影响抗氧化反应、自由基产生、细胞氧化损伤并影响 ECM BAV 主动脉来源的平滑肌细胞的产生、微结构和降解。在目标 2 中， 局部缺氧效应的量化、氧化细胞损伤的测量、ECM 微架构以及 生化 ECM 成分将进行区域比较，然后与患者特定的壁剪力相关 4D 血流 MRI 的应力测量、动态心电门控 CTA 的主动脉壁形态测量，以及 超声心动图的扩张性指标，用于开发可行的患者特异性多参数成像- 基于范式。该项目阶段的完成将生成一个主动脉生物图，描述机械和 BAV 相关主动脉病中氧化应激介导的 ECM 重塑，并将确定体内生物 成像终点与这些组织损伤相关。感知的可交付成果是一组构建块 可行的多参数计算模型，其主要输出是患者特定的主动脉完整性 评分可以更准确地识别特定患者的解剖风险。本作也将揭开新面纱 实施基于 PET 的探针以非侵入性方式检测局部主动脉脆弱性和 确定医学治疗干预的新目标。