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

创建瓣膜疾病工程模型以研究抗钙化疗法

• 批准号: 7590174
• 负责人: KRISTYN S MASTERS
• 金额: $ 31.74万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7590174
• 关键词: 3-Dimensional; Address; Adult; Adverse effects; Affect; Atherosclerosis; Biocompatible Materials; Bioprosthesis device; Calcified; Cardiovascular system; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Cholesterol; Clinical; Coenzyme A; Data; Disease; Disease Progression; Disease model; Drug Prescriptions; Elements; Engineering; Environment; Etiology; Extracellular Matrix; FDA approved; Failure; Functional disorder; Gel; Goals; Heart Valve Diseases; Heart Valves; Human; In Vitro; Investigation; Knowledge; Length; Mechanics; Medical; Medicine; Modeling; Organ; Oxidoreductase; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Population; Prevention; Property; Public Health; Role; Source; Staging; Stenosis; System; Testing; Time; Tissue Engineering; Tissues; Treatment Protocols; Work; aortic valve disorder; base; calcification; cytokine; dosage; improved; in vitro Model; in vitro testing; inhibitor/antagonist; interstitial cell; mineralization; model development; prevent; repaired; research study; response; scaffold; valve replacement

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.

描述（由申请人提供）：3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂或他汀类药物以其降低胆固醇的能力而闻名，是世界上最常用的处方药。虽然他汀类药物对抑制动脉粥样硬化的进展具有无可争议的积极作用，但最近关于他汀类药物对钙化性瓣膜狭窄（最常见的心脏瓣膜疾病类型）的影响出现了许多争议。由于许多因素，包括他汀类药物在全身的多效性（通常是矛盾的）作用，非常需要体外对照研究，以阐明他汀类药物对心脏瓣膜组织和功能的影响。因此，为了：（1）更好地了解瓣膜钙化的进展，（2）开发更多预防和治疗瓣膜钙化的选择，（3）更好地了解世界上处方最多的药物如何影响（和可能的好处）心脏瓣膜，我们的目标是建立离体和体外模型的瓣膜疾病，并在对照实验中使用这些模型来探索和表征他汀类药物对瓣膜功能的影响。以下具体目标将帮助我们实现这一目标：目的1：表征他汀类药物治疗对具有不同组成的体外培养物中的瓣膜间质细胞（维克）（dys）功能的影响。在目标1中，来自健康和患病来源的VIC将在限定组成的主要2-D环境中培养，用不同剂量的他汀类药物治疗不同的时间长度，然后检查钙化/功能障碍的指标。这些实验的结果将使我们能够理解他汀类药物如何调节维克功能障碍，培养物组合物在调节维克对他汀类药物的反应中的作用，以及他汀类药物的局限性/能力。目的2：创建和表征瓣膜疾病的三维模型。使用离体器官和体外细胞培养物，我们将通过多种不同的方法来产生患病瓣膜的生理相关模型。我们量身定制的患病瓣膜环境将提供一个可控且易于获得的培养系统，用于研究自体瓣膜疾病的进展以及各种药物对瓣膜功能的影响。目的3：利用离体和体外三维瓣膜病模型，评价以他汀类药物为基础的抗钙化治疗方案的疗效。在目标3中，我们将通过将目标1中确定的他汀类药物治疗方案应用于目标2中创建的“综合病变”瓣膜模型，将从目标1和目标2中获得的知识联合收割机结合起来。通过这些实验，我们将能够评估他汀类药物在生理相关环境中的能力和局限性，分析他汀类药物作用的中间阶段，并最终验证我们的模型作为抗钙化药物体外测试的平台是否有效。这项研究的结果可能具有重要的临床意义，因为拟议的工作解决了临床心血管修复的几个关键需求，例如更好地了解瓣膜疾病并探索治疗或抑制瓣膜狭窄的潜在疗法。这项工作的目标是研究他汀类药物，一种被全世界数百万人服用的降胆固醇药物，如何影响心脏瓣膜细胞的功能。这些实验直接适用于医学和公共卫生，因为它们将生成数据，从而能够更好地了解心脏瓣膜疾病的原因以及他汀类药物如何与心脏瓣膜相互作用的机制。我们的研究还将产生钙化性瓣膜病的体外模型，可用于测试其他抗钙化药物或策略。