Identifying the role of aortic valve interstitial cells and altered micro-environment on bicuspid aortic valve disease progression.

确定主动脉瓣间质细胞和改变的微环境对二叶式主动脉瓣疾病进展的作用。

基本信息

批准号：
10364606
负责人：
Alex Khang
金额：
$ 3.69万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-07-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY/ABSTRACT The bicuspid aortic valve (BAV) is the most common cardiac congenital defect and contains two, as opposed to the normal three, leaflet tissues. BAVs commonly become diseased at a faster rate than structurally normal aortic valves (AVs) most often due to calcium build up which eventually leads to aortic stenosis (AS). Current clinical treatments for AS in BAV patients consist only of surgical options such as AV repair and replacement, with replacement being the more common. Bioprosthetic valves are routinely used in replacement scenarios despite their limited lifespan of 10-15 years. In the context of BAV patients, who tend to disease at earlier time points in life, bioprosthetic valves are not an indefinite solution and will most likely require follow-up surgical operations. Alternatively, mechanical valves are employed for the younger BAV patient population but require the indefinite need for anticoagulants which substantially hinders patient quality of life. Thus, no optimal nor indefinite surgical intervention currently exists to treat BAV disease. Previous work from our lab and others have elucidated drastic differences in extracellular matrix (ECM) composition and structure as well as differences in the mechanical stress-strain environment between AVs and BAVs. However, it has yet to be elucidated as to how these changes affect BAV interstitial cell (BAVIC) functional remodeling behaviors. In addition, limited work has been done to explore whether BAV disease may be caused by intrinsic differences between the BAVICs and normal AV interstitial cells (AVICs). We hypothesize that the intrinsic differences of BAVICs, the altered microenvironment, and the altered BAV leaflet strains enhance BAV disease progression through cell-mediated ECM remodeling and biosynthesis brought on by phenotypic activation of the BAVIC population. We will address this hypothesis with the following three aims: Identifying the 3D morphological and ECM regional variations within the BAV. We will utilize state-of-the- art methods including 3D small angle light scattering, quantitative histology, and focused-ion beam scanning electron microscopy to assess the differences in ECM between the BAV and AV. Delineating the biophysical state and biosynthetic behaviors of isolated BAVICs and AVICs within peptide-modified poly (ethylene glycol) (PEG) hydrogels of varying stiffness. We will assess the contractile and biosynthetic properties of isolated BAVICs and AVICs within PEG hydrogels to investigate intrinsic differences among the cell groups. Emulating BAV leaflet strains to assess BAVIC remodeling behaviors in vitro. Here we will use a uniaxial stretch bioreactor to emulate BAV strain levels and assess how altered kinematics affect BAVIC responses.

项目摘要/摘要双尖瓣主动脉瓣（BAV）是最常见的心脏先天性缺陷，包含两个，而不是正常的三个传单组织。 BAV通常以比结构正常主动脉更快的速度患病瓣膜（AV）通常是由于钙的积累，最终导致主动脉狭窄（AS）。当前的临床 AS在BAV患者中的治疗仅包括手术选择，例如AV修复和替换，替代是更常见的。尽管他们有限的寿命为10 - 15年。在BAV患者的背景下，他们倾向于在早期的时间点病生命，生物假体瓣膜不是不确定的解决方案，很可能需要进行后续手术操作。另外，为年轻的BAV患者人群使用机械阀，但需要不确定需要抗凝剂，从而极大地阻碍了患者的生活质量。因此，没有最佳或无限期手术目前存在干预措施来治疗BAV疾病。我们实验室和其他人的先前工作已经阐明了剧烈的细胞外基质（ECM）组成和结构的差异以及机械的差异 AV和BAV之间的应力应变环境。但是，尚未阐明这些如何改变影响BAV间质细胞（BAVIC）功能重塑行为。此外，已经完成了有限的工作探索BAV疾病是否可能是由Bavics和正常AV之间的固有差异引起的间质细胞（AVICS）。我们假设Bavics的内在差异，改变的微环境，而变化的BAV小叶菌株通过细胞介导的ECM重塑增强了BAV疾病的进展和由巴维克人群的表型激活带来的生物合成。我们将解决这个假设以下三个目标：确定BAV内的3D形态和ECM区域变化。我们将利用最新艺术方法包括3D小角度散射，定量组织学和聚焦 - 离子束扫描电子显微镜评估BAV和AV之间的ECM差异。描述孤立的Bavics and Avics的生物物理状态和生物合成行为肽修饰的聚（乙二醇）（PEG）的刚度变化的水凝胶。我们将评估收缩 PEG水凝胶中分离的Bavics and Avics的生物合成特性，以研究内在细胞组之间的差异。模拟BAV小叶菌株以评估体外的Bavic重塑行为。在这里，我们将使用单轴拉伸生物反应器以模拟BAV应变水平并评估运动学改变如何影响BAVIC反应。