Roles Cell Phenotypes Myxomatous Mitral Valve Disease

描述(由申请人提供)：该项目的长期目标是了解二尖瓣粘液瘤改变的原因、机制和年龄相关性，改善二尖瓣粘液瘤患者的治疗选择，并减少人口中粘液瘤疾病的发生率。该项目的总体目标是鉴定和验证正常二尖瓣和粘液瘤二尖瓣分离细胞亚群的表型，并建立一种简单的粘液瘤变性细胞培养模型。粘液瘤型二尖瓣病变影响了5%的人群，随着年龄的增长，手术修复的累积需求增加。虽然在临床上得到了广泛的研究，但对粘液瘤瓣膜的组织学和生化研究仅限于特定类型的细胞外基质和细胞特性。这些以前的研究已经阐明了瓣膜病理的某些方面，但它们只暗示了可能是广泛的变化，他们还没有发现疾病的实际原因或测试任何潜在的疾病机制。因此，除了昂贵的手术或任何针对瓣膜疾病的药物外，没有治愈瓣膜疾病的方法。我们的中心假设是，特定的瓣膜细胞亚群负责粘液瘤的变化。瓣膜细胞的异质性已被广泛报道，但还没有显著的努力来纯化不同的瓣膜细胞亚群。因此，我们建议通过应用基于差异黏附的分离技术来分离这些亚群(目标1)来验证我们的假设，作为我们确定哪些细胞参与粘液瘤疾病中发现的基质重塑变化的第一步。我们还将通过与瓣膜组织的比较(目标2)和粘液瘤疾病的简单机械转导模型(目标3)来证实和功能测试这些细胞亚群的表型。我们预计，所开发的方法和模型将对粘液瘤型二尖瓣疾病进展的实验研究和心脏瓣膜生物学的发展产生重大影响。与公共卫生相关：治疗漏水、变形的二尖瓣会产生巨大的医疗费用，但这种疾病的原因尚不清楚。为了了解瓣膜变化的原因，我们计划在培养箱中培养二尖瓣细胞，并使用拉伸条件来模拟疾病的情况。

DESCRIPTION (provided by applicant): The broad long-term objectives of this project are to understand the cause, mechanism, and age dependence of myxomatous changes in mitral valves, to improve therapeutic options for myxomatous mitral valve patients, and reduce the incidence of myxomatous disease in the population. The overall goal of this project is to characterize and validate the phenotypes of isolated cell subpopulations from normal and myxomatous mitral valves and develop a simple cell culture model of myxomatous degeneration. Myxomatous mitral valve disease affects 5% of the population, with the cumulative need for surgical repair increasing with age. Although widely studied clinically, the histological and biochemical investigations of myxomatous valves have been limited to specific types of extracellular matrix and cell characteristics. These previous studies have illuminated certain aspects of valve pathology, but they only hint at what may be a wide spectrum of changes, and they have not found the actual cause of the disease or tested any potential disease mechanisms. As a result, there are no cures for valve disease other than expensive surgery, or any medications specific for valve disease. Our central hypothesis is that a specific subpopulation of the valvular cells is responsible for myxomatous changes. The heterogeneous nature of valvular cells has been widely reported, but there has been no significant effort to purify distinct subpopulations of valve cells. Therefore, we propose to investigate our hypothesis by applying differential adhesion-based separation techniques to isolate these subpopulations (Aim 1) as our first step towards determining which cells are involved in the matrix remodeling changes found in myxomatous disease. We will also corroborate and functionally test the phenotypes of these cell subpopulations through comparison with valve tissues (Aim 2) and through a simple mechanotransduction model of myxomatous disease (Aim 3). We expect that the developed methods and model will have significant impact on the development of experimental studies of the progression of myxomatous mitral valve disease and heart valve biology in general. Relevance to Public Health: Treatment of leaky, deformed mitral valves incurs significant health care costs, but the cause of this disease is unknown. To understand why the valve changes, we plan to grow cells from mitral valves in an incubator and use stretching conditions to mimic the circumstances of the disease.