Systems Biology of Fibroblast Activation Following Myocardial Infarction

 描述(申请人提供)：大约四分之一的心肌梗死(MI)患者进展为充血性心力衰竭，其5年死亡率为50%。该项目的目标是通过建立和验证成纤维细胞激活的时间演变的计算机计算模型来了解心肌梗死后成纤维细胞的作用。我们的初步结果表明，成纤维细胞在第一阶段经历了一系列的激活过程。 心肌梗死后28天，改变成纤维细胞的反应可以改变左心室(LV)的重构。我们假设成纤维细胞经历了一个时间表型演变来协调心肌梗死后左室重构的表型。我们的具体目标是：1)构建一个电子计算模型，模拟心肌梗死后成纤维细胞的激活模式；2)扰动内源性细胞因子和生长因子信号通路，以评估系统和优化模型的稳健性；以及3)检查内源性ECM的影响，以评估模型的可预测性。这一建议的创新之处既在于成纤维细胞作为一系列表型调节重塑的概念，也在于实验和计算方法的集成将使我们能够建立一种预测性计算工具。这些研究的潜在结果将是：1)开发一种模拟心肌梗死后成纤维细胞激活的计算工具；2)识别预测V重构结果的成纤维细胞激活标志物；3)认识可以通过治疗调节来调节成纤维细胞激活的关键纤维化机制。

 DESCRIPTION (provided by applicant): About one in four myocardial infarction (MI) patients progress to develop congestive heart failure, which has a 50% 5-year mortality rate. The goal of this project is to understand post-MI roles of the fibroblast by establishing and validating an in silico computational model of the temporal evolution of fibroblast activation. Our preliminary results demonstrate that fibroblasts proceed through a series of activation profiles over the first 28 days post-MI and that modifying fibroblast responses can alter remodeling of the left ventricle (LV). We hypothesize that fibroblasts undergo a temporal phenotype evolution to coordinate the post-MI LV remodeling phenotype. Our specific aims are: 1) construct an in silico computational model that simulates fibroblast activation patterns over the post-MI time course; 2) Perturb endogenous cytokine and growth factor signaling pathways to evaluate the system and optimize model robustness.; and 3) Examine endogenous ECM influences to evaluate model predictability. The innovation of this proposal lies in both the concept that fibroblasts regulate remodeling as a continuum of phenotypes and that integration of experimental and computational approaches will allow us to establish a predictive computational tool. The potential outcome of these studies will be 1) the development of a computational tool to simulate fibroblast activation post-MI; 2) the identification of fibroblast activation markers that predict V remodeling outcomes; and 3) recognition of key fibrotic mechanisms that can be therapeutically modulated to regulate fibroblast activation.