Ohio State - Nationwide Children's Hospital - Research For Muscle Biology and Disease

Rafael-FortneyJill A. Rafael-Fortney , Ph.D.

The Ohio State University
Department of Physiology & Cell Biology
Department of Biological Chemistry & Pharmacology
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 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.

Selected 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.
  • 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.
  • 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.
  • 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, J.A., 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. Epub 2012 May 1. 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." Neuromuscul. Disord Nov;22(11):1006-14. doi: 10.1016/j.nmd.2012.05.002. Epub 2012 Jun 29. PMID:22749475.
  • Murray, J.D., Canan, B.D., Martin, C.D., Stangland, J.E., Rastogi, N., Rafael-Fortney, J.A., Janssen, P.M. (2013) "The force- temperature relationship in healthy and dystrophic mouse diaphragm; implications for translational study design." Front Physiol. 2012;3:422. PMID:23162469.
  • Janssen PML*, Murray JD, Schill KE, Rastogi N, Schultz JE, Tran T, Raman SV, Rafael-Fortney JA*. (*equal contribution). (2014) Prednisolone attenuates improvement of cardiac and skeletal contractile function and histopathology by lisinopril and spironolactone in the mdx mouse model of Duchenne muscular dystrophy. PLoS One, Feb 13;9(2):e88360. PMID: 24551095.
  • Swager, S.A., Delfín, D.A., Rastogi, N., Wang, H., Canan, B.D., Fedorov, V.V., Mohler, P.J., Kilic, A., Higgins, R.S.D., Ziolo, M.T., Janssen, P.M.L., and Rafael-Fortney, J.A. (2015) "Claudin-5 levels are reduced from multiple cell types in human failing hearts and are associated with mislocalization of ephrin-B1", Cardiovasc. Pathol. 24(3):160-7. Epub 7 Nov 2014.
  • Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, Cripe LH. (2015) Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 14(2):153-61. Epub 2014 Dec 30. PMID: 25554404.
  • McNally EM, Kaltman JR, Benson DW, Canter CE, Cripe LH, Duan D, Finder JD, Hoffman EP, Judge DP, Kertesz N, Kinnett K, Kirsch R, Metzger JM, Pearson GD, Rafael-Fortney JA, Raman SV, Spurney CF, Targum SL, Wagner KR, Markham LW. (2015) Contemporary cardiac issues in Duchenne muscular dystrophy. Circulation 131(18):1590-8. PMID: 25940966.
  • Pant, M, Sopariwala, DH, Bal, NC, Lowe, J, Delfín, DA, Rafael-Fortney, JA, Periasamy, M. (2015) Metabolic dysfunction and altered mitochondrial dynamics in the utrophin-dystrophin deficient mouse model of Duchenne muscular dystrophy. PLoS One. Apr 10;10(4):e0123875. PMID:25859846.
  • Lowe, J., Wodarcyk, A. J., Floyd, K. T., Rastogi, N., Schultz, E. J., Swager, S. A., Chadwick, J. A., Tran, T., Raman, S. V., Janssen, P. M. L., and Rafael-Fortney, J. A. (2015) The angiotensin converting enzyme inhibitor lisinopril improves muscle histopathology but not contractile function in a mouse model of Duchenne muscular dystrophy. J. Neuromusc. Diseases 2: 257268.
  • Chadwick JA, Hauck JS, Lowe J, Shaw JJ, Guttridge DC, Gomez-Sanchez CE, Gomez-Sanchez EP, Rafael-Fortney JA. (2015) Mineralocorticoid Receptors are Present in Skeletal Muscle and Represent a Potential Therapeutic Target. FASEB J. 2015 Jul 15. pii: fj.15-276782.