Creating Engineered Models of Valvular Disease to Study Anti-Calcific Therapies

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DESCRIPTION (provided by applicant): 3-hydroxy-3-methyglutaryl-coenzyme A reductase inhibitors, or statins, are best known for their cholesterol-lowering abilities, and are the most prescribed drugs in the world. While statins have indisputably positive effects on inhibiting the progression of atherosclerosis, much controversy has recently arisen regarding the impact of statins on calcific valvular stenosis, the most common type of heart valve disease. Due to many factors, including the pleiotropic (and often paradoxical) effects of statins throughout the body, controlled in vitro studies are greatly needed in order to elucidate the effect of statins on heart valve tissue and function. Thus, in order to: (1) better understand the progression of valve calcification, (2) develop more options for prevention and treatment of valve calcification, and (3) better understand how the most prescribed drug in the world affects (and possibly benefits) heart valves, we aim to create ex vivo and in vitro models of valvular disease, and use these models in controlled experiments to explore and characterize the effects of statins on valve function. The following specific aims will help us to achieve this goal: AIM 1: Characterize the effects of statin treatment on valvular interstitial cell (VIC) (dys)function in in vitro cultures with varying compositions. In Aim 1, VICs from both healthy and diseased sources will be cultured in primarily 2-D environments of defined compositions, treated with different dosages of statins for varying lengths of time, and then examined for indicators of calcification/dysfunction. The results from these experiments will allow us to understand how statins regulate VIC dysfunction, the role of culture composition in regulating VIC response to statins, and the limitations/capabilities of statins. AIM 2: Create and characterize 3-D models of valvular disease. Using ex vivo organ and in vitro cell cultures, we will proceed through multiple different approaches to produce physiologically relevant models of diseased valves. Our tailored diseased valve environments will offer a controlled and readily-available culture system for studying the progression of native valve disease and the effects of various agents on valve function. AIM 3: Using 3-D ex vivo and in vitro models of valvular disease, evaluate the efficacy of statin- based anti-calcification treatment regimens. In Aim 3, we will combine the knowledge gained from Aims 1 and 2 by applying the statin treatment regimens identified in Aim 1 to the `synthetically-diseased' valve models created in Aim 2. Through these experiments, we will be able to evaluate statin capabilities and limitations in physiologically-relevant environments, analyze intermediate stages of statin action, and, ultimately, validate whether our models are effective as platforms for in vitro testing of anti-calcific drugs. The results of this investigation are likely to have significant clinical implications, as the proposed work addresses several critical needs in clinical cardiovascular repair, such as gaining a better understanding of valvular disease and exploring potential therapies to treat or inhibit valvular stenosis. The goal of the proposed work is to study how statins, cholesterol-lowering drugs which are taken by millions of people worldwide, affect the function of heart valve cells. These experiments are directly applicable to medicine and public health in that they will generate data that will enable a better understanding of the causes of heart valve disease and the mechanism of how statins interact with heart valves. Our study will also generate in vitro models of calcific valvular disease that may be used for testing other anti-calcification pharmaceuticals or strategies.