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发作（心肌梗死）。对于大多数在最初事件中幸存下来的人来说，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。瘢痕组织是由心脏成纤维细胞产生的，我们最近发现瘢痕结构和机械性能在愈合过程中受到机械拉伸的强烈影响。成纤维细胞如何响应单个信号（如机械拉伸）的生物学已经得到了广泛的研究;然而，我们对成纤维细胞如何整合和响应愈合伤口中存在的多种信号仍然知之甚少。因此，我们开发了一种基于试剂的疤痕形成模型（ABM），该模型代表单个成纤维细胞-每个成纤维细胞都会迁移、排列、沉积和重塑胶原蛋白，分裂、死亡，并根据实验测量对单个化学、结构和机械信号做出反应-并预测不同拉伸模式下疤痕愈合中组织水平胶原蛋白含量和纤维排列的演变。在这里，我们建议耦合此ABM与梗死左心室的有限元模型（FEM），以产生耦合模型，该模型可以预测梗死后的瘢痕结构，瘢痕力学和心脏功能之间的动态相互作用，并响应于改变梗死力学的治疗（目标1）。然后，我们将使用实验和建模相结合，以更好地了解机械拉伸调节胶原蛋白含量和对齐愈合心肌梗死的细胞机制。具体而言，我们将测试以下假设：胶原降解的机械调节显著影响机械卸载期间的胶原含量和排列（目标2），瘢痕压实显著影响胶原纤维密度，但在一系列加载条件下不影响平面内纤维排列（目标3）。拟议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生成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瘢痕形成的细胞机制提供重要的新见解，这可能导致识别调节梗塞愈合的新治疗方法。

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.