Jefferson Research Collaborative Receives $11.6 Million NIH Program Project Grant to Study Novel Mechanisms of Heart Failure
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.
Media Only Contact:
Richard Cushman
Thomas Jefferson University Hospital
Phone: (215) 955-6300
Published: 5/6/2008