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. ? ? ?
