Systems Biology of Fibroblast Activation Following Myocardial Infarction

心肌梗塞后成纤维细胞激活的系统生物学

• 批准号: 9119340
• 负责人: MERRY L LINDSEY
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119340
• 关键词: American; Cardiac; Cell model; Cell physiology; Cells; Cicatrix; Classification; Collagen; Computer Simulation; Congestive Heart Failure; Coupled; Data; Development; Diagnosis; Evolution; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibronectins; Flow Cytometry; Foundations; Goals; Grant; Growth; Healed; Heart; Heart failure; In Vitro; Infarction; Inflammation; Inflammatory; Integrins; Interleukin-1; Knowledge; Left ventricular structure; Leukocytes; Matrix Metalloproteinases; Mediator of activation protein; Modeling; Molecular; Myocardial Infarction; Myofibroblast; Outcome; Outcome Study; Output; Patients; Pattern; Phase; Phenotype; Population; Production; Regulation; Role; Running; Series; Signal Pathway; Signal Transduction; Stimulus; Structure; System; Systems Biology; Testing; Time; Transforming Growth Factor beta; Ventricular Remodeling; Wound Healing; base; cell type; chemokine; computerized tools; cytokine; glycoproteomics; healing; high risk; improved outcome; in vivo; innovation; mathematical model; mortality; new therapeutic target; next generation sequencing; periostin; predicting response; prevent; public health relevance; research study; response; simulation; therapy development; transcriptomics

 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.

 描述（由申请人提供）：大约四分之一的心肌梗塞 (MI) 患者会发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时间演化的计算机模型来了解成纤维细胞在 MI 后的作用。我们的初步结果表明，成纤维细胞在第一个过程中经历了一系列激活过程 MI 后 28 天，改变成纤维细胞反应可以改变左心室 (LV) 的重塑。我们假设成纤维细胞经历时间表型进化以协调 MI 后 LV 重塑表型。我们的具体目标是：1）构建一个计算机模型，模拟 MI 后时间过程中的成纤维细胞激活模式； 2) 扰乱内源性细胞因子和生长因子信号通路以评估系统并优化模型稳健性； 3) 检查内源 ECM 影响以评估模型的可预测性。该提案的创新之处在于成纤维细胞将重塑作为表型的连续体来调节的概念，以及实验和计算方法的整合将使我们能够建立预测计算工具。这些研究的潜在结果将是：1）开发一种计算工具来模拟心肌梗死后成纤维细胞的激活； 2) 鉴定预测 V 重塑结果的成纤维细胞活化标记物； 3) 认识到可以通过治疗调节来调节成纤维细胞活化的关键纤维化机制。