R01HL162925

Systems Pharmacology Model of Cardiac Hypertrophy - Summary

Heart failure is defined as the inability of cardiac output to meet demand. Moreover, heart failure causes significant morbidity and mortality, affecting over 6 million Americans, with approximately 50% mortality at five years despite current pharmacologic and device-based therapies.

Cardiac hypertrophy, defined as an increase in cardiomyocyte size and heart muscle mass, leads to maladaptive remodeling and is a significant precursor of heart failure. Thus, intervening early during cardiac hypertrophy has the potential to improve the health and outcomes of patients.

For decades, investigations have characterized individual intracellular molecular regulators of cardiac hypertrophy; however, effective clinical therapies specifically targeting cardiac hypertrophy remain elusive. We aim to overcome the past obstacles of focusing on a single signaling molecule by employing a systems approach that considers the more extensive network of signaling interactions and FDA-approved drugs that are viable candidates for drug repurposing.

Our overall goal is to identify drugs and network mechanisms as therapeutic targets to control cardiac hypertrophy. To achieve this goal, we will test the overall hypothesis that a systems pharmacology network model can accurately predict the context-dependent effects of drugs on cardiomyocyte hypertrophy in vitro and in vivo.

In Specific Aim 1, we will apply a systems pharmacology model to predict drugs and drug combinations that cause context-dependent regulation of cardiomyocyte hypertrophy. We will develop a computational model that integrates the cardiomyocyte signaling network with the pharmacologic mechanisms of FDA-approved drugs. We will then use this model to predict the drug combinations and network mechanisms that inhibit cardiomyocyte hypertrophy under distinct environmental contexts.

In Specific Aim 2, we will validate our model predictions of candidate drugs using cultured rat and human cardiomyocytes to test the context-dependent inhibition of cardiomyocyte hypertrophy.

In Specific Aim 3, we will translate the model and cell-based experimental data to in vivo mouse models of cardiac hypertrophy and determine whether the modeling accurately predicts the effects of drugs in a context-dependent manner.

Overall, these studies will establish a systems pharmacology model, provide new computational insights into how drugs modulate cardiac hypertrophy, and generate a wealth of new experimental data that will validate these predictions.

Rector & Visitors Of The University Of Virginia

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Charlottesville, Virginia 229044195 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 305% from $761,655 to $3,081,718.