Computational Modeling of Scar Formation After Myocardial Infarction

心肌梗塞后疤痕形成的计算模型

• 批准号: 8629133
• 负责人: JEFFREY W HOLMES
• 金额: $ 37.3万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629133
• 关键词: American; Anisotropy; Biology; Cardiac; Cells; Chemicals; Cicatrix; Collagen; Collagen Fiber; Computer Simulation; Coupled; Cytoskeleton; Data; Deposition; Development; Elements; Environment; Event; Evolution; Experimental Models; Fiber; Fibroblasts; Goals; Healed; Heart; Heart failure; In Vitro; Individual; Infarction; Injection of therapeutic agent; Lead; Left ventricular structure; Measurement; Measures; Mechanics; Modeling; Myocardial Infarction; Myocardium; Operative Surgical Procedures; Patients; Pattern; Polymers; Property; Regulation; Research Personnel; Rest; Risk; Role; Rupture; Signal Transduction; Stimulus; Stretching; Structure; Testing; Therapeutic Intervention; Time; Tissues; Work; Wound Healing; base; density; design; healing; heart function; improved; in vivo; innovation; insight; migration; multi-scale modeling; new therapeutic target; novel; novel therapeutic intervention; predictive modeling; public health relevance; research study; response; restraint; screening; therapy design; tool

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.

每年有超过一百万的美国人心脏病发作（心肌梗塞）。对于大多数人 在初始事件中生存，严重并发症（例如梗塞破裂和心力衰竭）的风险 取决于取代受损心脏的疤痕组织的结构和机械性能 肌肉在头几周。疤痕组织是由心脏成纤维细胞产生的，我们最近 表明疤痕结构和机械性能受到机械拉伸的强烈影响 在康复期间。成纤维细胞如何响应单个信号（例如机械拉伸）的生物学 已经广泛研究了；然而，我们仍然对成纤维细胞的整合和 响应愈合伤口中存在的多个信号。因此，我们开发了一个基于代理的 代表单个成纤维细胞的疤痕形成模型（ABM） - 每个迁移，对准， 沉积和重塑胶原蛋白，分裂，垂死并响应单个化学，结构， 根据实验测量值和机械信号 - 并预测所得的进化 在不同的拉伸模式下，疤痕愈合中组织水平的胶原蛋白含量和纤维对齐。 在这里，我们建议将此ABM与梗塞左心室的有限元元素模型（FEM）搭配到 产生一个耦合模型，该模型可以预测不断发展的疤痕结构之间的动态相互作用 力学和梗塞后心脏功能以及响应改变梗塞力学的疗法 （目标1）。然后，我们将使用实验和建模的组合来更好地了解细胞 机械拉伸调节胶原蛋白含量和愈合中对齐的机制 心肌梗塞。具体而言，我们将测试胶原蛋白的机械调节的假设 降解在机械卸载过程中显着影响胶原蛋白的含量和对齐（目标 2），疤痕压实显着影响胶原蛋白纤维密度，但面积内纤维不影响 在一系列加载条件下对齐（AIM 3）。拟议的研究可能是重要的 这两者都是因为它们将在一系列范围内生成第一个经过验证的梗死愈合的预测模型 机械条件 - 实现新疗法的计算筛查和设计 - 和 因为它们将为细胞机制提供重要的新见解 环境调节疤痕形成，这可能导致新的治疗性识别 调节梗塞愈合的方法。