Systems Pharmacology Model for Spatial Control of Cardiac Fibrosis

心脏纤维化空间控制的系统药理学模型

基本信息

批准号：
9363220
负责人：
JEFFREY W HOLMES
金额：
$ 47.97万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9363220
关键词：
Acute Address American Arrhythmia Cardiac Cell model Cells Cicatrix Collagen Computer Simulation Congestive Heart Failure Databases Deposition Devices Drug Combinations Drug Controls Drug Targeting Educational workshop Employee Strikes Environment Event Experimental Models Extracellular Matrix Extracellular Protein Failure Fibroblasts Fibrosis Goals Heart Heart failure Heterogeneity Impairment In Vitro Individual Infarction Inflammation Inflammatory Injectable Injury Left Life Location Modeling Muscle Myocardial Infarction Myocardium National Heart, Lung, and Blood Institute Organ Pharmaceutical Preparations Pharmacology Polymers Preclinical Drug Evaluation Preparation Pump Rattus Regimen Regulation Risk Rupture Series Signal Transduction Site Specificity System Testing Time United States National Institutes of Health Ventricular Ventricular Fibrillation Vision Wound Healing base coronary fibrosis experience experimental study healing heart pharmacology improved in vivo injured innovation interstitial molecular drug target multi-scale modeling network models novel novel strategies novel therapeutic intervention response spatiotemporal virtual

项目摘要

The majority of individuals that initially survive a myocardial infarction go on to suffer from life-threatening complications such as infarct rupture, arrhythmia, or heart failure. These sequelae depend critically on wound healing in the infarct as well as fibrosis in the remote myocardium, yet existing drugs are not designed to specifically target either of these. An ideal pharmacologic therapy would enhance extracellular matrix in the infarct while reducing fibrosis in the remote myocardium, but achieving such spatial control of extracellular matrix has eluded the field. We propose that these distinct local responses to globally applied drugs can be achieved by leveraging environment-dependent signaling mechanisms, uniquely identified with systems pharmacology models. We first integrate drug-target interaction databases together with a novel large-scale model of the cardiac signaling network to identify drugs or drug pairs that cause context-dependent regulation of extracellular matrix with cultured cardiac fibroblasts. We then integrate the signaling network model with agent-based models of inflammation and myocardial infarct healing. This integrated model is applied to perform multi-scale virtual drug screening to predict and then experimentally validate drugs that enhance extracellular matrix in the infarct while reducing fibrosis in the remote myocardium. Overall, this study will provide an innovative framework for multi-scale systems pharmacology of cardiac fibrosis, identify new therapeutic approaches for infarct healing, and provide proof-of-concept for spatial control of drug responses by leveraging context-dependent cell signaling.

大多数最初在心肌梗塞中幸存下来的人会继续危及生命梗塞破裂，心律不齐或心力衰竭等并发症。这些后遗症严重取决于伤口梗塞和纤维化中的愈合远程心肌，但现有药物并非旨在特别针对其中的任何一个。理想的药理疗法将增强细胞外基质在减少远程心肌纤维化的同时梗塞，但要实现这种细胞外的空间控制矩阵已经避开了领域。我们建议这些对全球申请药物的局部反应可能是通过利用环境依赖性信号传导机制实现，并用系统独特地识别药理学模型。我们首先将药品目标交互数据库与一个新颖的大规模集成心脏信号网络的模型，以识别引起背景调节的药物或药物对具有培养的心脏成纤维细胞的细胞外基质。然后，我们将信号网络模型与基于代理的炎症和心肌梗塞愈合模型。该集成模型应用于进行多尺度的虚拟药物筛查以预测，然后实验验证可以增强的药物梗塞中的细胞外基质，同时减少遥远心肌的纤维化。总体而言，这项研究将为心脏纤维化的多尺度系统药理学提供创新的框架，确定新的梗塞愈合的治疗方法，并为药物反应的空间控制提供了概念验证通过利用背景依赖性单元信号传导。