Jill A. Rafael-Fortney

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Associate Professor

Ph.D. - University of Michigan
Post Doctoral - University of Oxford

The overall goal of my laboratory is to identify novel treatment strategies for Duchenne muscular dystrophy (DMD), a disease that affects both skeletal muscles and the heart. We use mouse models to unravel the molecular pathogenesis of DMD, identify novel molecular treatment targets, and test potential therapeutic approaches.

Using a mouse model of DMD, we identified a protein called claudin-5 to be reduced during the earliest steps of cardiomyopathy. We then found that claudin-5 is also present at reduced levels in the majority of patients with heart failure from all etiologies. Maintaining normal claudin-5 levels is able to prevent the early physiological and histological hallmarks of heart failure in the mouse model where reductions were first observed. Current research in the lab is focused on identifying whether claudin-5 is sufficient to cause heart failure, understanding its mechanism of action in normal and diseased heart, and optimizing its therapeutic potential for DMD and other forms of cardiomyopathy.

We also test a variety of potential gene therapy, peptide, and pharmacological therapeutic approaches for their effects on dystrophic skeletal muscles and heart using a comprehensive set of in vivo and in vitro approaches. Most recently, we have identified that prophylactic treatment with standard-of-care heart failure drugs can prevent striated muscle damage in dystrophic mice. Current research on this project is focused on unraveling the mechanisms of action of these heart failure drugs on skeletal muscles with the ultimate goal of designing novel therapeutic approaches for muscular dystrophy and other causes of muscle weakness.

Recent Representative Publications:

• 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 2005 June 17.
• 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.
• Zhou L, Rafael-Fortney JA, Huang P, Zhao XS, Cheng G, Zhou X, Kaminski HJ, Liu L, Ransohoff RM. (2008) Haploinsufficiency of utrophin gene worsens skeletal muscle inflammation and fibrosis in mdx mice., J Neurol Sci. Jan 15;264(1-2):106-11.
• 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, 10;39(3):343-349.
• Xu, Y., Delfín, D., Rafael-Fortney, J.A., and Janssen, P.M.L. (2011) "Lengthening-contractions in isolated myocardium impact force development and worsen cardiac contractile function in the mdx mouse model of muscular dystrophy". J. Appl. Physiol. Feb;110(2):512-9. Epub 2010 Dec 2. PMID: 21127205
• Verhaert, D., Richards, K., Rafael-Fortney, J.A. and Raman, S.V. (2011) “Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations”, Circ Cardiovasc Imaging. 2011 Jan;4(1):67-76. PMID: 21245364.
• Peterson JM, Kline W, Canan BD, Ricca DJ, Kaspar B, Delfín DA, Dirienzo K, Clemens PR, Robbins PD, Baldwin AS, Flood P, Kaumaya P, Frietas M, Kornegay JN, Mendell JR, Rafael-Fortney JA, Guttridge DC, Janssen PM. (2011) "Peptide-based inhibition of NF-kB rescues diaphragm muscle contractile dysfunction in a murine model of Duchenne muscular dystrophy." Mol. Med 5-6;17(5-6):508-515. PMID: 21267511.
• Delfín, D.A.*, Xu, Y. *, Peterson, J.M. *, Guttridge, D.C.#, Rafael-Fortney, J.A.#, and Janssen, P.M.L. #. (*/# equal contribution) (2011) "Improvement of cardiac contractile function by peptide-based inhibition of NF-kB in the utrophin/dystrophin-deficient murine model of muscular dystrophy", J. Transl. Med. 9:68. PMID: 21586145.
• Rafael-Fortney, J.A. *, Chimanji, N.S., Schill, K.E., Martin, C.D., Murray. J.D., Ganguly, R., Stangland, J.E., Tran, T., Xu, Y., Canan, B.D., Mays, T.A., Delfín, D.A., Janssen, P.M.L. *, Raman, S.V. (*Equal Contributions) " Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne Muscular Dystrophy mice.", Circulation, 124:582-588. Epub 2011 July 18. PMID: 21768542.
• Delfín, D.A., Xu, Y., Schill, K.E., Mays, T.A., Canan, B.D., Zang, K.E., Barnum, J.A., Janssen, P.M.L., and Rafael-Fortney, J.A. (2012) "Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model." Mol. Ther., Jul;20(7):1378-83. doi: 10.1038/mt.2012.81. PMID: 22547149.
• Delfín, D.A., Zang, K.E., Schill, K.E., Patel, N.T., Janssen, P.M., Raman, S.V., and Rafael-Fortney, J.A. (2012) "Cardiomyopathy in the dystrophin/utrophin-deficient mouse model of severe muscular dystrophy is characterized by dysregulation of matrix metalloproteinases." Neuromusc. Disord Nov;22(11):1006-14. doi: 10.1016/j.nmd.2012.05.002. Epub 2012 Jun 29. PMID:22749475