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Jill A. Rafael-Fortney , Ph.D.
Associate Professor
The Ohio State University
Department of Molecular and Cellular Biochemistry
Department of Physiology & Cell
Biology
Division of Cardiovascular Medicine,
Department of Internal Medicine
1645 Neil Avenue
Columbus, Oh 43210
Phone: (614) 292-7043
Email:
rafael-fortney.1@osu.edu
Education & Training:
Cornell University, B.A.
University of Michigan Ph.D. in
Human Genetics
University of Oxford,
Postdoctoral Fellow
Research Interest:
The goals of my laboratory are to delineate the pathogenic mechanisms
of neuromuscular diseases in order to design rational approaches for treatments. Our
lab focuses on two different basic science projects: 1) Identification
of novel molecular targets for the treatment of cardiomyopathy and heart
failure; and 2) Understanding the functions of the membrane-associated
guanylate kinase scaffolding
proteins Dlg and CASK in skeletal muscle and their role in neuromuscular diseases.
Cardiomyopathy
Although the vast majority of research has focused on
the pathogenesis and treatment of the debilitating skeletal muscle weakness
in Duchenne muscular dystrophy (DMD), the majority of patients also develop
dilated cardiomyopathy and at least 25% currently die from heart failure. We
have identified a specific reduction of claudin-5 only in hearts of the
utrophin/dystrophin-deficient (dko) mouse model of muscular dystrophy and
heart failure. The transmembrane claudin-5 cell junction protein
is normally present at lateral membranes of cardiomyocytes at their junction
with extracellular matrix, a connection affected early in the process of
ventricular remodeling in heart failure. Claudin-5 is almost entirely
deficient only from cardiomyocytes in dko mice at the age they begin to
exhibit heart failure. Claudin-5 levels are also reduced in 60% of
cardiac samples obtained from freshly explanted human end-stage failing
hearts of diverse etiologies. These claudin-5 reductions are independent
of changes in other cell junction proteins and other previously identified
protein alterations in heart failure. These data support that claudin-5
represents a key switch from many forms of cardiomyopathy to progression
of heart failure. The current focus of this project is on defining
whether claudin-5 represents a target for novel therapeutic approaches
for heart failure.
CASK and Dlg
Membrane-associated guanylate kinases (MAGUKs) serve as
scaffold proteins at cell junctions and synapses. We have shown that CASK localizes
to both the pre- and post-synaptic membranes of the neuromuscular junction,
where it forms a complex with another MAGUK, Dlg. We have gone on
to show that CASK undergoes relocalization from the nucleus to the cytoplasm
during development in a myogenic cell line and that both CASK and Dlg localize
to nuclei in a motor neuron cell line. CASK and Dlg are also recruited
to the neuromuscular junction independent of acetylcholine receptor complexes. These
studies delineate important developmental characteristics of CASK and Dlg
and suggest dual roles for these proteins in both the skeletal muscle and
motor neuron components of the neuromuscular junction. From our in
vivo studies, we have identified the localization of previously known
CASK and Dlg neuronal interactors at the post-synaptic neuromuscular junction,
including most surprisingly, glutamate receptors of both the NMDA and AMPA
subtypes. Since CASK and Dlg are both essential genes in mammals,
our current studies focus on muscle-specific knockouts of these MAGUK proteins
to identify their functions in different cellular compartments of muscle
fibers and during muscle development
Selected Publications:
- Sanford, J.L., Mays, T.A., and Rafael-Fortney, J.A. (2004) CASK and
Dlg form a PDZ protein complex at the mammalian neuromuscular junction. Muscle & Nerve 30:164-171.
- Sanford, J.L., Edwards, J.D., Mays, T.A., Gong, B., Merriam, A.P.
and Rafael-Fortney, J.A. (2005) Claudin-5 localizes to the lateral
side of cardiomyocytes and is altered in utrophin/dystrophin-deficient
cardiomyopathic mice., J. Mol. Cell. Cardiol., 38:323-332.
- Gardner, K.L., Sanford, J.L., Mays, T.A., and Rafael-Fortney, J.A.
(2006) CASK localizes to nuclei in developing skeletal muscle and motor
neuron culture models and is agrin-independent. J. Cell. Physiol., 206(1):196-202.
Epub June 17, 2005.
- Janssen, P.M.L., Hiranandani, N., Mays, T.A., and Rafael-Fortney,
J.A. (2005) Utrophin deficiency worsens cardiac contractile dysfunction
present in dystrophin-deficient mdx mice. Am J Physiol Heart Circ
Physiol., 289(6):H2373-8. Epub 2005 Jul 15.
- Gardner, K.L., Kearney, J.A., Edwards, J., and Rafael-Fortney, J.A.
(2006) Restoration of all dystrophin protein interactions by functional
domains in trans does not rescue dystrophy. Gene Ther. 13(9):744-51.
- Baker, P.E., Kearney, J.A., Gong, B., Merriam, A.P., Kuhn, D.E.,
Porter, J.D. and Rafael-Fortney, J.A. (2006) Analysis of gene expression
differences between utrophin/dystrophin-deficient versus mdx skeletal
muscles reveals a specific upregulation of slow muscle genes in limb
muscles. Neurogenetics. 7(2):81-91. Epub 2006 Mar 9.
- Sanford, J.L., Mays, T.A., Varian, K.D., Wilson, J.B., Janssen, P.M.L.,
and Rafael-Fortney, J.A. (2008) Truncated CASK does not alter
skeletal muscle or protein interactors. Muscle & Nerve, 38(3):1116-27.
- Mays, T.A., Binkley, P.F., Lesinski, A., Doshi, A.A., Quaile, M.P.,
Margulies, K.B., Janssen, P.M.L., and Rafael-Fortney, J.A. (2008) Claudin-5
levels are reduced in human end-stage cardiomyopathy. J. Mol. Cell.
Cardiol., 45(1):81-7. Epub 2008 Apr 25.
- Mays, T.A., Sanford, J.L.,
Hanada, T., Chishti, A.H., and Rafael-Fortney, J.A. (2009) Glutamate
receptors localize post-synaptically at neuromuscular junctions in
mice. Muscle & Nerve, 39: 343-349.
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