# Systems Pharmacology Model for Spatial Control of Cardiac Fibrosis

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $481,612

## Abstract

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.

## Key facts

- **NIH application ID:** 9983802
- **Project number:** 5R01HL137755-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** JEFFREY W HOLMES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $481,612
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983802

## Citation

> US National Institutes of Health, RePORTER application 9983802, Systems Pharmacology Model for Spatial Control of Cardiac Fibrosis (5R01HL137755-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9983802. Licensed CC0.

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