Jill 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
Education & Training:
Cornell University, B.A.
University of Michigan Ph.D. in
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.
- 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. (2011) " 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.
- Janssen PML*, Murray JD, Schill KE, Rastogi N, Schultz EJ, Tran T, Raman SV, Rafael-Fortney JA*. (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.
- 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 Nov;29(11):4544-54. PMID: 26178166.
- Lowe, J, Floyd, KT, Rastogi, N, Schultz, EJ, Chadwick, JA, Swager, SA, Zins, JG, Kadakia, FK, Smart, S, Gomez-Sanchez, EP, Gomez-Sanchez, CE, Raman, SV, Janssen, PM&, Rafael-Fortney, JA&. (&equal contribution) (2016) Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice. J Neuromusc Diseases, 3: 395–404. PMID: 27822449.
- Chadwick, JA, Swager, SA, Welc, S, Lowe, JA, Gomez-Sanchez, EP, Gomez-Sanchez, CE, Tidball, JA, and Rafael-Fortney, JA. (2016) Myeloid cells are capable of synthesizing aldosterone to exacerbate damage in muscular dystrophy. Hum Mol Genet., 2016 Dec 1;25(23):5167-5177. doi: 10.1093/hmg/ddw331. PMID: 27798095.
- Milani-Nejad N, Schultz EJ, Slabaugh JL, Janssen PM, Rafael-Fortney JA. (2017) Myocardial Contractile Dysfunction is Present without Histopathology in a Mouse Model of Limb-Girdle Muscular Dystrophy-2F and is Prevented after Claudin-5 Virotherapy. Front Physiol. 2016 Dec 6;7:539. doi: 10.3389/fphys.2016.00539. eCollection 2016.
- Chadwick, JA, Bhattacharya, S, Lowe, J, Weisleder, N, and Rafael-Fortney, JA. (2017) Renin-angiotensin-aldosterone system inhibitors improve membrane stability and change gene expression profiles in dystrophic skeletal muscles, Am J Physiol Cell Physiol., 2017 Feb 1;312(2):C155-C168. doi: 10.1152/ajpcell.00269.2016. PMID: 27881412.
- Chadwick, JA, Hauck, JS, Gomez-Sanchez, C.E., Gomez-Sanchez, E.P. and Rafael-Fortney, JA. (2017) Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle. Physiol Genomics, 2017 Jun 1;49(6):277-286. doi: 10.1152/physiolgenomics.00128.2016. Epub 2017 Apr 21. PMID: 28432191.
My NCBI Link: http://www.ncbi.nlm.nih.gov/sites/myncbi/jill.rafael-fortney.1/bibliography/45600091/public/?sort=date&direction=ascending