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100多万美国人心脏病发作(心肌梗死)。对于大多数人来说 在最初的事件中幸存下来，有严重并发症的风险，如梗塞破裂和心力衰竭 取决于取代受损心脏的疤痕组织的结构和机械性能 在最初的几周里肌肉发达。疤痕组织是由心脏成纤维细胞产生的，我们最近 结果表明，机械拉伸对瘢痕组织和力学性能有很大影响 在康复过程中。成纤维细胞如何对机械拉伸等个体信号作出反应的生物学 已经被广泛研究；然而我们仍然对成纤维细胞如何整合和 对愈合伤口中存在的多重信号做出反应。因此，我们开发了一种基于代理的 代表单个成纤维细胞的瘢痕形成模型(ABM)-每个成纤维细胞迁移、排列、 沉积和重塑胶原蛋白，分裂，染色，并对个别化学物质，结构， 和机械信号，根据实验测量-并预测由此产生的进化 不同拉伸方式下瘢痕愈合过程中组织层胶原含量和纤维排列的变化。 在这里，我们建议将这种ABM与左心室梗死的有限元模型(Fem)相结合，以 建立一个耦合模型，该模型可以预测不断演变的SCAR结构、SCAR 心肌梗塞后的力学和心功能，以及对改变梗塞力学的治疗的反应 (目标1)。然后，我们将使用实验和建模的结合来更好地理解细胞 机械拉伸调节愈合过程中胶原含量和排列的机制 心肌梗死。具体地说，我们将测试胶原蛋白的机械调节假说 降解显著影响机械卸载过程中的胶原含量和排列(目的 2)瘢痕致密对胶原纤维密度有显著影响，但对面内纤维无明显影响。 在一系列加载条件下对齐(目标3)。拟议的研究具有潜在的重要意义。 两者都是因为它们将生成第一个经过验证的、预测脑梗塞愈合的模型 机械条件--使计算机筛选和设计新疗法成为可能--以及 因为它们将提供对细胞机制的重要新见解，通过这些机制 环境调节瘢痕的形成，这可能导致新的治疗方法的确定 调控心肌梗死愈合的方法。