Systems Pharmacology Model of Heart Failure with Preserved Ejection Fraction
Abstract
Heart failure with preserved ejection fraction (HFpEF) affects more than 3 million people in the United States (~1% of the population) and carries a 75% 5-year mortality. In HFpEF patients, while the heart is able to contract normally, it is too stiff to fill properly. There is currently a lack of evidence-based therapies for HFpEF; this is in part due to its complex heterogenous nature, which makes identification of drugs/therapies challenging. There is therefore an urgent need to develop novel therapeutic drugs to reverse HFpEF. Such a drug would provide unprecedented hope to both civilian and military patients who have limited options in their battle against HFpEF. Traditionally, efforts to combat cardiac diseases have focused on a single causative gene, which we believe is not the ideal approach when it comes to a multifactorial disease such as HFpEF. Hence, in this proposal, we will employ a systems approach that considers the more extensive network of signaling interactions and U.S. Food and Drug Administration (FDA)-approved drugs that are viable candidates for drug repurposing. Instead of targeting a single gene, we will generate a genome-wide transcriptional signature of genes that are perturbed in HFpEF and apply a systems pharmacology model to predict drugs that cause a broad reversal of genes that are dysregulated in HFpEF. Our early experiments using a single model of HFpEF have shown promising results by identifying novel compounds that can reverse impaired relaxation of cardiac cells. We will expand our pipeline to include more models of HFpEF including mice, rats, and human transcriptomic data, and test predicted compounds for their potency in alleviating HFpEF both in vitro and in vivo. Overall, these studies will establish a systems pharmacology model, new computational insights into how drugs modulate cardiac diastolic dysfunction, and a wealth of new experimental data that will validate these predictions.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310104
Entities
People
- Sang Ging Ong
Organizations
- United States Army
- University of Illinois at Chicago