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ROS Mechanisms in BAV Aortopathy

BAV 主动脉病中的 ROS 机制

基本信息

批准号：
10675526
负责人：
Thomas Gillette Gleason
金额：
$ 71.82万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/10675526
关键词：
4D MRI Acute Affect Aneurysm Angiography Antioxidants Aorta Architecture Biochemical Biological Biology Biomechanics Cardiac Surgery procedures Caring Cause of Death Clinical Clinical Trials Collagen Complex Computer Models Coupled Data Diameter 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 Non-Invasive Detection Operative Surgical Procedures Output Oxidative Stress Oxidative Stress Induction Oxidative Stress Pathway Oxygen Patient Care Patient risk Patients Phase Pimonidazole Play Positron-Emission Tomography Predisposition Preventive Production Publishing Recommendation 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 adjudication aortic valve ascending aorta base bicuspid aortic valve bioimaging cell injury clinical imaging cohort congenital anomaly design diagnostic tool 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.

项目总结升主动脉瘤样疾病是一个世界性的重大健康问题。二尖瓣主动脉瓣(BAV) 相关的主动脉病变是受影响患者中最大的一组，这种先天异常是存在的。占总人口的1%-2%。目前以主动脉直径为基础的外科干预指南源于自然病史数据的非受控外推，不能反映患者特有的主动脉病变有可能导致一些患者治疗不足，另一些患者治疗过度。这在很大程度上是因为对与BAV相关的生物和生物力学特征的了解不完全大动脉病变或其他退行性动脉瘤，以及这些侮辱如何加剧主动脉夹层。在.期间在之前的资助期间，我们发现了几个基于细胞、组织结构和生物力学的特征 BAV相关性大动脉病变与退行性动脉瘤的鉴别。我们发现高处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，以及结合各向异性胶原和弹性蛋白的生物力学强度分布微体系结构独一无二地定义了BAV主动脉的组织微环境。在下一阶段的项目中，我们将阐明机械和氧化应激的相互作用如何介导ECM重塑，确定低氧在哪里起作用，以及临床影像衍生指标如何与细胞和 BAVs主动脉内的组织异常。在两个目标的方法中，我们将检验机械的中心假设外力和局部缺氧诱导的氧化应激引起BAV和TAV不同的ECM重塑患者，这些侮辱可以与患者特定的主动脉壁指数相关联，这些指数可以成像、捆绑并用于预测疾病进展和/或主动脉灾难。目标1‘S的方法将采用我们的建立了针对患者的3D培养模型，以确定机械拉伸和低氧分压影响抗氧化反应、自由基产生、细胞氧化损伤，并影响细胞外基质兔腹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，细胞外基质微结构，以及生化ECM成分将进行地区性比较，然后与患者特定的壁切变相关联来自4D Flow MRI的应力测量，来自动态心电门控CTA的主动脉壁形态测量，以及来自超声心动图的扩张性指标，以开发可操作的针对患者的多参数成像- 基于范例。这一项目阶段的完成将生成一份主动脉生物图谱，该图谱描述了机械和氧化应激介导的ECM在BAV相关性主动脉病变中的重塑，并将确定在体内成像终点与这些组织侮辱相关。感知到的可交付成果是一组构建块，用于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分数。这项工作还将揭示新的实施基于PET的探头非侵入性检测局部主动脉脆弱性的机会和确定医疗干预的新靶点。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Extracellular matrix fiber microarchitecture is region-specific in bicuspid aortic valve-associated ascending aortopathy.

DOI：
10.1016/j.jtcvs.2016.02.019
发表时间：
2016-06
期刊：
The Journal of thoracic and cardiovascular surgery
影响因子：
0
作者：
Tsamis A;Phillippi JA;Koch RG;Chan PG;Krawiec JT;D'Amore A;Watkins SC;Wagner WR;Vorp DA;Gleason TG
通讯作者：
Gleason TG

Layer-specific Nos3 expression and genotypic distribution in bicuspid aortic valve aortopathy.

二叶式主动脉瓣主动脉病中层特异性 Nos3 表达和基因型分布。

DOI：
10.1093/ejcts/ezac237
发表时间：
2022
期刊：
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
影响因子：
0
作者：
Hill,JenniferC;Billaud,Marie;Richards,TaraD;Kotlarczyk,MaryP;Shiva,Sruti;Phillippi,JulieA;Gleason,ThomasG
通讯作者：
Gleason,ThomasG

Mechanism of aortic medial matrix remodeling is distinct in patients with bicuspid aortic valve.

DOI：
10.1016/j.jtcvs.2013.04.028
发表时间：
2014-03
期刊：
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
影响因子：
6
作者：
Phillippi, Julie A.;Green, Benjamin R.;Eskay, Michael A.;Kotlarczyk, Mary P.;Hill, Michael R.;Robertson, Anne M.;Watkins, Simon C.;Vorp, David A.;Gleason, Thomas G.
通讯作者：
Gleason, Thomas G.

Distal Extent of Surgery for Acute Type A Aortic Dissection.