# Systems Biology of Hypertrophic Heart Disease from Molecular Pathways to Organ System

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $465,018

## Abstract

Abstract
This proposal will integrate novel cell signaling models of myocyte hypertrophy into organ-level continuum
models of ventricular growth, remodeling and mechanoenergetics coupled to hemodynamic models of
systemic hypertension. The multi-scale computational models, together with experiments in rats subjected
to ventricular hemodynamic overload, will be used to investigate the interactions between anisotropic
stretch and neurohormonal signaling pathways in the development of eccentric ventricular hypertrophy,
fibrosis and hypertension-induced cardiac remodeling. Specifically, we will use genome-scale data from
pressure-overloaded rat hearts to refine and validate quantitative models of hypertrophic regulatory
networks. We will use proteomic and transcriptomic measurements from aortic-banded and sham-operated
rat hearts to test and refine quantitative systems models of anisotropic stretch- and neurohormonally-
simulated cardiac myocyte hypertrophy in vivo. We will also model and validate tissue- and organ-scale
growth and remodeling of the heart due to ventricular pressure overload. We will couple cardiovascular
system-models of whole body hemodynamics to three-dimensional continuum models of ventricular growth
and remodeling driven by hypertrophic signaling models and cell-scale growth laws. Large-scale data sets
from high-field diffusion-tensor magnet resonance imaging in the rat, and constrained mixture models, add
detailed information on fiber architecture and material properties. Finally, we will predict
mechanoenergetic consequences of ventricular hypertrophy. Models will be extended to include remodeling
of contractility and energy metabolism pathways, and used to predict alterations in myocardial
mechanoenergetics during pressure overload. These model predictions will then be validated with extensive
characterization of in-vivo mechanics (by tagged magnetic resonance imaging) and energetics. These new
models will be validated and optimized to help define and analyze specific hypertrophic pathways relevant
to translational outcomes in hypertensive patients, with the ultimate potential of identifying new diagnostic
biomarkers and therapeutic targets for hypertensive heart disease.

## Key facts

- **NIH application ID:** 9856457
- **Project number:** 5R01HL137100-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Andrew D. McCulloch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $465,018
- **Award type:** 5
- **Project period:** 2017-02-13 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856457

## Citation

> US National Institutes of Health, RePORTER application 9856457, Systems Biology of Hypertrophic Heart Disease from Molecular Pathways to Organ System (5R01HL137100-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856457. Licensed CC0.

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