ROS mechanisms in BAV aortopathy

BAV 主动脉病中的 ROS 机制

基本信息

批准号：
9884346
负责人：
Thomas Gillette Gleason
金额：
$ 79.7万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884346
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

项目摘要

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.

项目摘要升高主动脉瘤性是全球主要的健康问题。双刺主动脉瓣（BAV） - 相关的主动脉肿大是受影响患者的最大子集，并且存在该先天性异常在1-2％的普通人群中。目前的基于主动脉干预的基于主动脉的直径准则，源于自然历史数据的非控制外推，不反映患者特异性主动脉灾难某些患者的风险施用不足和其他患者的过度治疗。这主要是因为有对哪些生物学和生物力学特征是与BAV相关的独特的不完全理解主动脉肿大或其他退化性动脉瘤以及这些侮辱如何增强主动脉夹层。在先前的资金期，我们发现了几个细胞，组织结构和基于生物力学的特征区分BAV相关的主动脉瘤与退化性动脉瘤的主动脉瘤。我们发现高架内侧平滑肌细胞生产超氧化阴离子，增加氧化应激诱导的细胞损坏和生物力学强度曲线以及各向营养的胶原蛋白和弹性蛋白微体系结构独特地定义了BAV主动脉的组织微环境。在下一阶段项目，我们将阐明机械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相对应 BAV主动脉中的组织像差。在两种AIM的方法中，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用BAV和TAV中的差异ECM重塑患者，这些侮辱可以与可以成像，捆绑的患者特异性主动脉壁指数相关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已建立的患者特异性3D培养模型，以确定机械拉伸和低氧张力如何影响抗氧化剂反应，自由基产生，细胞氧化损伤并影响ECM BAV主动脉衍生的平滑肌细胞的生产，微体系结构和降解。在AIM 2中，量化局部缺氧作用，氧化细胞损伤的测量，ECM微体系结构和生化ECM组成将在区域比较，然后与患者特异性壁剪相关来自4D流MRI，动态ECG门控CTA的主动脉壁形态计量学和应力测量超声心动图的可扩展指标以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产生一个主动脉映射，该主动脉映射介绍机械和氧化应激介导的ECM重塑与BAV相关的主动脉疾病，将确定体内生物体内什么成像终点与这些组织侮辱相关。感知到的可交付是一组构建块可行的多参数计算模型的主要输出将是患者特定主动脉完整性得分更准确地确定给定患者的解剖风险。这项工作也将揭示新的实施基于宠物的探针以非侵入性检测局部主动脉脆弱性和确定医学治疗干预的新目标。