ROS mechanisms in BAV aortopathy

BAV 主动脉病中的 ROS 机制

基本信息

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

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Thomas Gillette Gleason其他文献

Thomas Gillette Gleason的其他文献

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{{ truncateString('Thomas Gillette Gleason', 18)}}的其他基金

ROS Mechanisms in BAV Aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    10675526
  • 财政年份:
    2021
  • 资助金额:
    $ 69.68万
  • 项目类别:
ROS Mechanisms in BAV Aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    10733581
  • 财政年份:
    2021
  • 资助金额:
    $ 69.68万
  • 项目类别:
ROS Mechanisms in BAV Aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    8464218
  • 财政年份:
    2012
  • 资助金额:
    $ 69.68万
  • 项目类别:
ROS Mechanisms in BAV Aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    9058113
  • 财政年份:
    2012
  • 资助金额:
    $ 69.68万
  • 项目类别:
ROS Mechanisms in BAV Aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    8292372
  • 财政年份:
    2012
  • 资助金额:
    $ 69.68万
  • 项目类别:
ROS mechanisms in BAV aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    9884346
  • 财政年份:
    2012
  • 资助金额:
    $ 69.68万
  • 项目类别:
ROS Mechanisms in BAV Aortopathy
BAV 主动脉病中的 ROS 机制
  • 批准号:
    8842688
  • 财政年份:
    2012
  • 资助金额:
    $ 69.68万
  • 项目类别:
BACTERIAL EXPOSURE, T CELLS AND SURGICAL INFECTION
细菌暴露、T 细胞和手术感染
  • 批准号:
    2059565
  • 财政年份:
    1996
  • 资助金额:
    $ 69.68万
  • 项目类别:

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