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

摘要

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.