(PHILADELPHIA) – Scientists at Jefferson Medical College have received a five-year, $11.6 million grant from the National Heart, Lung and Blood Institute to study molecular mechanisms of cardiac injury that lead to heart failure and potential repair processes that occur in the adult failing heart. This project aims to find data that can be translated into novel therapeutic strategies to improve the failing heart.
“This study is unique in that we’re not only studying factors that contribute to heart failure but we are also looking for cellular and molecular mechanisms that promote repair for the damaged heart,” said principal investigator Walter J. Koch, PhD., the W.W Smith Professor of Medicine and director of the Center for Translational Medicine in the Department of Medicine at Jefferson Medical College of Thomas Jefferson University. “We will have four core facilities and four different labs working on this grant from a host of different angles. While much of the project will focus on the science of failure and repair, it is also clinically relevant in that we are working with stem cells and pharmaceutical drugs already being given to patients.”
An advantage of this type of NIH Program Project Grant is that the four primary projects can be supported by core units. This grant supports four core areas: administrative, surgical, molecular and gene therapy and four main laboratories. In addition to Dr. Koch’s leadership in these areas, leaders of these facilities are Andrea Eckhart, Ph.D., Patrick Most, M.D., Erhe Gao, M.D., Ph.D. and Joseph Rabinowitz, Ph.D., all faculty members in the Center for Translational Medicine.
Dr. Koch’s group is studying how the enzyme GRK5, which plays a novel role in heart cell signaling and function, is involved in regulating heart cell gene transcription. Gene transcription is part of the two-step process that cells use to read a gene and produce a protein. According to Dr. Koch, abnormal increases in gene transcription are involved in heart failure and heart enlargement.
Another group led by Arthur Feldman, M.D., PhD., the Magee Professor and Chair of Medicine at Jefferson Medical College, will focus on the role of adenosine receptors in the heart. While much is known about their role in protecting the heart when it’s deprived of oxygen during a heart attack, little is known about what part it plays in healing the heart after injury and in heart failure. Two major adenosine receptor types in the heart appear to have opposite effects. Chronic signaling through one type appears to be detrimental to the heart, resulting in heart failure; whereas signaling through the other receptor appears beneficial. Too much expression of the latter can help repair a heart in failure. Dr. Feldman’s research team wants to more closely study the adenosine receptors in the failing heart.
Steven R. Houser, PhD., chair of the Department of Physiology and director of the Cardiovascular Research Center at Temple University’s School of Medicine, will investigate how the influx of calcium ions can potentially damage the heart or aid in its regeneration, depending on the calcium channels involved. Previous data indicates that an influx of calcium through one type (L) of channel can increase heart damage in the failing heart. But Dr. Houser has found that within the adult heart there are small cells that appear to come from resident cardiac stem cells. These heart cells depend on the (T) type calcium channel and probably aid in normal heart regeneration, though there are too few to repair the heart during a heart attack. Dr. Houser would like to study the calcium signaling characteristics of these heart stem cells to try to understand what mobilizes them, and he is seeking to understand their regenerative potential.
Thomas Force, M.D., the James C. Wilson Professor of Medicine at Jefferson Medical College, has found that a certain type of cancer drug called a tyrosine kinase inhibitor (including the very successful leukemia drug Gleevec), which interferes with a particular enzyme, can cause heart failure. But because the damage appears to be reversible, one theory says that the drugs, instead of damaging the heart cells, may actually hurt heart stem cells and prevent repair. Some early results in the laboratory with stem cell cultured with Gleevec seem to support the theory. Dr. Force’s group will continue to test the tyrosine kinase inhibitor drugs to better understand how they affect cardiac stem cells.