Temple scientists receive $11.5 million grant for heart failure research

Innovative treatments for heart failure are lacking, leaving the nearly six million Americans who suffer from the condition with little hope for a cure. But thanks to an $11.5-million Program Project Grant (PPG) from the National Heart, Lung, and Blood Institute (NHLBI), scientists at Temple University School of Medicine are now set to further their investigation of key molecular mechanisms in heart failure, an effort that is expected to lead to the development of new heart therapies.

The Principal Investigator on the new PPG award is Dr. Walter J. Koch, PhD, The William Wikoff Smith Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, and Director of the Center for Translational Medicine at Temple University School of Medicine (TUSM). Dr. Koch is working alongside two other Temple researchers on the Program Project Grant – Dr. Steven R. Houser, PhD, FAHA, Senior Associate Dean for Research, Professor and Chair of the Department of Physiology, and Director of the Cardiovascular Research Center at TUSM; and Dr. Arthur M. Feldman, MD, PhD, Executive Dean of TUSM, and Chief Academic Officer of Temple University Health System.

Each of the scientists is leading a specific project for the grant, with all three projects being natural outgrowths of ongoing research in their individual laboratories. The three projects focus on signaling pathways implicated in cardiac injury and repair, and they likely intersect in heart failure pathology, underscoring the significance of the collaborative research effort.

"The Program Project Grant give us the opportunity to develop novel approaches to treat ischemic heart disease," explained Dr. Houser. "Our goal will be to have new therapeutics ready for patients through our PPG."

The new award represents the second round of PPG funding for the three researchers. Over the course of their previous funding cycle, Drs. Feldman, Houser, and Koch developed highly integrated research programs aimed at better understanding the signaling molecules involved in heart failure. Their preliminary research resulted in the identification of the three signaling pathways that the researchers are now investigating for the second PPG. Those pathways center on an enzyme known as G-protein coupled receptor kinase 5 (GRK5) and on molecules known as arginine vasopressin (AVP) type 1A receptors and transient receptor potential (TRP) channels.

GRK5 forms the basis of Dr. Koch's portion of the PPG. In earlier work, he and colleagues found that the enzyme, which normally resides in the cytoplasm of heart cells, can be transported into the heart cell nucleus. There, in the cockpit of the cell, GRK5 takes control over the activity of certain genes. Its manipulations ultimately cause heart cells to increase in size, creating a condition known as hypertrophy, which is a central feature of heart failure.

Dr. Feldman's PPG research explores the role of AVP type 1A receptors in cardiac injury. In previous work in mice, Feldman's team found that the density of AVP receptors increases in the heart following cardiac injury. The change in receptor expression was associated with diminished heart function. In the next steps of investigation, Feldman hopes to elucidate the mechanism underlying that association.

Dr. Houser's project is focused on TRP channels and the role of calcium signaling in cardiac hypertrophy and tissue remodeling in heart failure. Following ischemia, which temporarily deprives the heart of oxygen, TRP channels are expressed at abnormally high levels. Dr. Houser suspects that the change in channel expression increases calcium entry into heart cells, leading to maladaptive remodeling processes such as hypertrophy.

The suspected point of intersection for the three pathways is with AVP receptor signaling. Activation of AVP receptors mediates heart cell damage during cardiac injury but may also initiate repair mechanisms based on G protein and GRK regulation. As a result, the activity of AVP receptors, as well as GRK5 and TRP channels, which are turned on by G proteins, could be influenced therapeutically to favor cellular repair in the failing heart.

The new round of PPG funding comes at a key time. The number of Americans who suffer from heart failure is expected to increase from five million to ten million by 2031. That increase will be accompanied by a significant rise in deaths from the condition, if new therapies are not developed soon.

Temple is a key site for the origination of those much-needed treatments. When the first PPG was awarded, Drs. Feldman and Koch were based at Thomas Jefferson University, located a few miles from Dr. Houser's laboratory at Temple. Now, all three scientists are in the same building, Drs. Feldman and Koch having relocated to Temple. The proximity of the research teams allows for an unprecedented level of interaction in heart failure research at Temple's Center for Translational Medicine and Cardiovascular Research Center.

"The PPG is of great importance to Temple," explained Dr. Feldman. "It provides not only funding for specific projects but also supports state-of-the-art core facilities and a platform for team science, both of which are critical to success in this era of translational science."