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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：
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
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/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

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