RSK3-mAKAP Targeting as a New Therapeutic Strategy for Heart Failure with Preserved Ejection Fraction in Women
Abstract
This application addresses a current issue of great significance in the area of Women’s Heart Disease, the current lack of treatments for Heart Failure with Preserved Ejection Fraction (HFpEF). Heart failure contributes to the death of about 1 in 8 Americans. Heart failure is currently associated with a 50% chance of death within 5 years of the onset of symptoms despite improvements in the care of heart failure patients and the use of such drugs as ACE inhibitors and beta-blockers. This project will obtain initial proof-of-concept for a new biologic drug intended to treat chronic heart disease. The new drug is especially promising as a new therapy for HFpEF, a form of heart failure that disproportionately affects women. Because of the association of HFpEF with women, this proposal is especially relevant to our female former and current active duty personnel, including Reservists and National Guard members. In addition, as post-traumatic stress syndrome is more common in women and is a risk factor for the development of heart failure, this project will be of particular relevance to that subset of affected women Veterans. The development of effective HFpEF therapies has been impeded by a lack of relevant animal models that effectively model this complex disease. Due to its similar anatomy and cardiac function, the pig has long been the gold standard for preclinical experimentation relevant to cardiovascular disease in humans. The laboratory led by Dr. Craig Emter at the University of Missouri has recently developed a novel swine model that is similar to human HFpEF, including the presence of clinically relevant non-heart abnormalities. The Ossabaw pig raised on a high-fat “Western diet” is a validated model of obesity, diabetes, and high cholesterol-associated vascular disease. We have adapted this model to HFpEF by adding a surgical procedure in females to create the research equivalent of high blood pressure. Exciting new data demonstrate how this pig model exhibits the major characteristics of human HFpEF, allowing us to study therapies specifically for this form of heart failure. While the Emter lab has been developing large animal models for heart failure, the laboratory led by Dr. Michael Kapiloff at Stanford University has been identifying molecular and cellular regulatory mechanisms that are responsible for the deterioration of heart function in disease. In particular, they have identified two molecules, called RSK3 and mAKAP, as critical for the progression of heart disease in mice. A result of their studies has been the development of a new biologic drug called “RBD.” This drug has been found to be remarkably effective in mice at preventing heart failure. In this project led jointly by Dr. Emter and Dr. Kapiloff, RBD will be tested in the female Ossabaw pig model for HFpEF, determining whether the new drug can prevent HFpEF. These studies will both reveal whether this new drug should continue to be developed as a new therapy for human disease, while also providing new information about the mechanisms contributing to heart failure. The preliminary data upon which this application is predicated suggest that targeting the RSK3-mAKAP regulatory pathway will provide an unprecedented opportunity to prevent the deaths of women afflicted with heart failure.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810178
Entities
People
- Michael S Kapiloff
Organizations
- Stanford University
- United States Army