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.

项目概要/摘要二叶式主动脉瓣 (BAV) 是最常见的心脏先天性缺陷，包含两个，而不是正常三、小叶组织。 BAV 患病的速度通常比结构正常的主动脉更快瓣膜（AV）最常见的原因是钙积聚，最终导致主动脉瓣狭窄（AS）。目前临床 BAV 患者的 AS 治疗仅包括手术选择，例如 AV 修复和置换，更换更为常见。尽管生物瓣膜通常用于置换场景它们的使用寿命有限，为 10-15 年。对于 BAV 患者，他们倾向于在早期时间点发病在生活中，生物瓣膜并不是一个无限期的解决方案，很可能需要后续外科手术。或者，机械瓣膜可用于年轻的 BAV 患者群体，但需要无限期的抗凝药物的需求严重影响了患者的生活质量。因此，没有最佳或无限期的手术目前存在治疗 BAV 疾病的干预措施。我们实验室和其他人之前的工作已经阐明了细胞外基质（ECM）组成和结构的差异以及机械性能的差异 AV 和 BAV 之间的应力应变环境。但这些变化是如何发生的，目前尚不清楚影响 BAV 间质细胞 (BAVIC) 功能重塑行为。此外，还开展了有限的工作探讨 BAV 疾病是否可能由 BAVIC 与正常 AV 之间的内在差异引起间质细胞（AVIC）。我们假设 BAVIC 的内在差异、改变的微环境、改变的 BAV 小叶菌株通过细胞介导的 ECM 重塑增强 BAV 疾病进展以及 BAVIC 群体表型激活引起的生物合成。我们将解决这个假设实现以下三个目标：识别 BAV 内的 3D 形态和 ECM 区域变化。我们将利用最先进的艺术方法，包括 3D 小角度光散射、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 ECM 的差异。描述分离的 BAVIC 和 AVIC 的生物物理状态和生物合成行为不同硬度的肽改性聚乙二醇（PEG）水凝胶。我们将评估收缩性 PEG 水凝胶中分离的 BAVIC 和 AVIC 的生物合成特性，以研究其内在特性细胞群之间的差异。模拟 BAV 小叶菌株以评估 BAVIC 体外重塑行为。这里我们将使用单轴拉伸生物反应器来模拟 BAV 应变水平并评估改变的运动学如何影响 BAVIC 反应。