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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：大约四分之一的心肌梗塞（MI）患者发展出充血性心力衰竭，其5年死亡率为50％。该项目的目的是通过建立和验证成纤维细胞激活暂时演变的计算机计算模型来了解成纤维细胞的MI后角色。我们的初步结果表明，成纤维细胞通过第一个激活曲线进行 MI后28天和修饰成纤维细胞反应可以改变左通气的重塑（LV）。我们假设成纤维细胞经历临时表型演化，以协调MI LV重塑表型。我们的具体目的是：1）在MI后时间过程中模拟成纤维细胞激活模式中的硅计算模型中构建一个； 2）扰动内源性细胞因子和生长因子信号传导途径，以评估系统并优化模型鲁棒性。 3）检查内源性ECM的影响以评估模型可预测性。该提案的创新在于成纤维细胞调节重塑为表型连续体的概念，实验和计算方法的整合将使我们能够建立一个预测性的计算工具。这些研究的潜在结果将是1）开发了MI后模拟成纤维细胞激活的计算工具； 2）鉴定预测V重塑结果的成纤维细胞激活标记； 3）识别可以热调节以调节成纤维细胞激活的关键纤维化机制。