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: 8916817
• 负责人: JEFFREY W HOLMES
• 金额: $ 36.52万
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916817
• 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; Health; 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; research study; response; restraint; screening; therapy design; tool

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.

描述（由申请人提供）：每年有超过一百万美国人遭受心脏病发作（心肌梗塞）。对于大多数在最初事件中幸存下来的人来说，梗塞破裂和心力衰竭等严重并发症的风险取决于最初几周内替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，我们最近表明疤痕结构和机械性能受到愈合过程中机械拉伸的强烈影响。成纤维细胞如何响应机械拉伸等个体信号的生物学已被广泛研究。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代理的疤痕形成模型（ABM），代表单个成纤维细胞 - 每个成纤维细胞根据实验测量迁移、排列、沉积和重塑胶原蛋白、分裂、死亡，并对单个化学、结构和机械信号做出反应 - 并且预测不同拉伸模式下疤痕愈合过程中组织级胶原蛋白含量和纤维排列的演变。在这里，我们建议将该 ABM 与梗塞左心室的有限元模型 (FEM) 耦合，以生成一个耦合模型，该模型可以预测梗塞后不断演变的疤痕结构、疤痕力学和心脏功能之间的动态相互作用，并响应改变梗塞机制的疗法（目标 1）。然后，我们将结合实验和建模来更好地了解机械拉伸调节胶原蛋白含量和排列以治愈心肌梗塞的细胞机制。具体来说，我们将测试以下假设：胶原蛋白降解的机械调节显着影响机械卸载期间的胶原含量和排列（目标 2），并且疤痕压实显着影响胶原纤维密度，但不会影响一系列负载条件下的平面内纤维排列（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塞愈合预测模型，从而实现新疗法的计算筛选和设计，并且因为它们将为细胞机制提供重要的新见解。机械环境调节疤痕形成，这可能导致确定调节梗塞愈合的新治疗方法。