Computational Modeling of Scar Formation After Myocardial Infarction

描述（由申请人提供）：每年有超过一百万的美国人患有心脏病（心肌梗死）。对于大多数在最初的事件中幸存下来的人来说，发生严重并发症（如梗死破裂和心力衰竭）的风险取决于在最初几周内取代受损心肌的疤痕组织的结构和机械特性。疤痕组织是由心脏成纤维细胞产生的，我们最近发现，在愈合过程中，疤痕的结构和机械性能受到机械拉伸的强烈影响。成纤维细胞如何对个体信号（如机械拉伸）做出反应的生物学已经得到了广泛的研究；然而，对于成纤维细胞如何整合和响应愈合伤口中的多种信号，我们仍然知之甚少。因此，我们开发了一种基于agent的疤痕形成模型（ABM），该模型代表单个成纤维细胞-根据实验测量，每个成纤维细胞迁移，排列，沉积和重塑胶原蛋白，分裂，死亡并响应个体化学，结构和机械信号-并预测在不同拉伸模式下疤痕愈合过程中组织水平胶原蛋白含量和纤维排列的最终演变。在这里，我们建议将这种ABM与梗死左心室的有限元模型（FEM）相结合，以产生一个耦合模型，该模型可以预测梗死后疤痕结构、疤痕力学和心功能之间的动态相互作用，以及对改变梗死力学的治疗的反应（目的1）。然后，我们将结合实验和建模来更好地理解机械拉伸调节胶原蛋白含量和愈合心肌梗死排列的细胞机制。具体来说，我们将验证以下假设：在机械卸载过程中，胶原蛋白降解的机械调节显著影响胶原蛋白含量和排列（目的2）；在一系列加载条件下，疤痕压实显著影响胶原纤维密度，但不影响面内纤维排列（目的3）。提出的研究具有潜在的重要意义，因为它们将在一系列机械条件下产生第一个经过验证的梗死愈合预测模型-使计算筛选和设计新疗法成为可能-并且因为它们将为机械环境调节疤痕形成的细胞机制提供重要的新见解，这可能导致确定调节梗死愈合的新治疗方法。

DESCRIPTION (provided by applicant): Over a million Americans suffer a heart attack (myocardial infarction) each year. For the majority who survive the initial event, the risks of serious complications such as infarct rupture and heart failure depend on the structure and mechanical properties of the scar tissue that replaces damaged heart muscle over the first few weeks. That scar tissue is produced by cardiac fibroblasts, and we recently showed that scar structure and mechanical properties are strongly influenced by mechanical stretch during healing. The biology of how fibroblasts respond to individual signals such as mechanical stretch has been studied extensively; yet we still understand relatively little about how fibroblasts integrate and respond to the multiple signals present in a healing wound. We therefore developed an agent-based model (ABM) of scar formation that represents individual fibroblasts - each migrating, aligning, depositing and remodeling collagen, dividing, dying, and responding to individual chemical, structural, and mechanical signals according to experimental measurements - and predicts the resulting evolution of tissue-level collagen content and fiber alignment in scars healing under different patterns of stretch. Here, we propose to couple this ABM with a finite-element model (FEM) of the infarct left ventricle to produce a coupled model that can predict the dynamic interplay between evolving scar structure, scar mechanics, and heart function after infarction and in response to therapies that alter infarct mechanics (Aim 1). Then, we will use a combination of experiments and modeling to better understand the cellular mechanisms by which mechanical stretch regulates collagen content and alignment in healing myocardial infarcts. Specifically, we will test the hypotheses that mechanical regulation of collagen degradation significantly influences collagen content and alignment during mechanical unloading (Aim 2) and that scar compaction significantly influences collagen fiber density but not in-plane fiber alignment across a range of loading conditions (Aim 3). The proposed studies are potentially significant both because they will generate the first validated, predictive model of infarct healing across a range of mechanical conditions - enabling computational screening and design of novel therapies - and because they will provide important new insight into the cellular mechanisms by which mechanical environment regulates scar formation, which could lead to the identification of new therapeutic approaches to modulating infarct healing.