The Effect of Mechanical Stimuli on Mitral Valve Interstitial Cell Phenotypic State in Myxomatous Valve Disease

机械刺激对粘液瘤性瓣膜病二尖瓣间质细胞表型状态的影响

• 批准号: 9328616
• 负责人: Salma Ayoub
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328616
• 关键词: Address; Affect; Anabolism; Anterior; Biomechanics; Bioreactors; Cell physiology; Cells; Clinical; Clinical Treatment; Computer Simulation; Data; Disease; Disease Progression; Elements; Etiology; Exhibits; Failure; Goals; Homeostasis; Human; In Situ; In Vitro; Knowledge; Lead; Link; Measures; Mechanical Stress; Mechanics; Mitral Valve; Mitral Valve Insufficiency; Modeling; Operative Surgical Procedures; Pathologic; Pharmacological Treatment; Phenotype; Physiological; Recurrence; Research; Research Project Grants; Stimulus; Stress; Structure; System; Techniques; Tissue Engineering; Tissues; Work; base; experimental study; human tissue; improved; in vivo; insight; interstitial cell; mechanical load; novel; novel strategies; outcome prediction; repaired; response

PROJECT SUMMARY In the mitral valve (MV) several pathological factors such as mitral regurgitation (MR) and degenerative myxomatous mitral valve disease (MMVD), have been shown to affect tissue structure and composition. Current clinical treatments for both functional and degenerative MR include ring annuloplasty. Though beneficial in the short-term, it has been shown to be less promising in the long term, with repair failure as high as 60%. Mechanical stress is a strong etiological factor: alterations in mechanical loading caused by surgical repair lead to stress-induced changes in valve interstitial cell (VIC) function that affect both tissue structure and composition, ultimately leading to repair failure. The link between tissue-level stresses and cellular homeostatic response is essential in understanding valve disease progression and in developing novel approaches to improve surgical repair. We thus hypothesize that mitral VIC (MVIC) deformation is a major driver for cellular mechanoregulation, and that abnormal mechanical stimuli lead to non-physiological MVIC deformations that result in phenotypic activation and altered biosynthetic activity. Extending these ideas for pathological valve conditions, we further hypothesize that myxomatous MVICs can exhibit signs of phenotypic reversal after being exposed to a physiological strain regime in a healthy microenvironment. Exploiting this knowledge can lead to improved surgical repair techniques for both functional and degenerative MR. We will address our hypotheses with the following two aims: (1) Investigate the response of normal MVICs to a range of physiological and non-physiological biaxial loading conditions. First, using intact ovine MV anterior leaflets. Then, by utilizing a human MVIC seeded engineered-tissue approach to characterize the responses of normal human MVICs to biaxial loading conditions. (2) Characterize the response of human myxomatous MVICs to physiological and non-physiological biaxial loading conditions. Building upon our hypothesis that MVIC deformation drives homeostatic response, we will use our established MV macro-micro finite element model to simulate in vivo MVIC deformation under different surgical repair scenarios and bracket physiological and non-physiological regions within the range of in vitro biaxial loading conditions used in (1). We will then explore the potential to induce phenotypic reversal in myxomatous MVICs after an in vitro treatment in an optimal mechano-microenvironment.

项目摘要 在二尖瓣（MV）中，几种病理因素，如二尖瓣返流（MR）和退行性病变， 粘液瘤性二尖瓣疾病（MMVD）已经显示影响组织结构和组成。 目前功能性和退行性二尖瓣返流的临床治疗包括瓣环成形术。虽然 虽然它在短期内是有益的，但从长远来看，它的前景不太乐观，修复失败率高达 60%。机械应力是一个很强的病因：手术引起的机械负荷的改变 修复导致瓣膜间质细胞（维克）功能的应力诱导变化， 最终导致修复失败。组织水平应激与细胞稳态之间的联系 在了解瓣膜疾病进展和开发新的治疗方法方面， 改进外科修复。因此，我们假设二尖瓣维克（MVIC）变形是细胞凋亡的主要驱动因素。 机械调节，并且异常机械刺激导致非生理MVIC变形， 导致表型活化和改变的生物合成活性。将这些想法扩展到病理性瓣膜 我们进一步假设粘液瘤性MVIC在被治疗后可以表现出表型逆转的迹象。 暴露于健康微环境中的生理应变状态。利用这些知识可以导致 改进功能性和退行性MR的手术修复技术。我们将讨论我们的假设 有以下两个目标： (1)研究正常MVIC对一系列生理和非生理双轴的反应 加载条件首先，使用完整的绵羊二尖瓣前叶。然后，通过利用人类MVIC， 表征正常人MVIC对双轴的反应的种子工程组织方法 加载条件 (2)表征人粘液瘤MVIC对生理和非生理性 双轴加载条件根据我们的假设，MVIC变形驱动体内平衡 响应，我们将使用我们建立的MV宏微观有限元模型来模拟体内MVIC 在不同手术修复情况下的变形以及支架生理和非生理 在（1）中使用的体外双轴载荷条件范围内的区域。然后我们将探索 在最佳条件下体外治疗后，诱导粘液瘤MVIC表型逆转的潜力 机械微环境。