Paul M.L. Janssen, Ph.D.
200/206 Hamilton Hall
1645 Neil Avenue
Columbus, Ohio 43210-1218
Ph.D., combined program between Wake Forest University, NC, University of Illinois at Chicago, and Utrecht University, the Netherlands.
The main research interests in my lab are the mechanisms that govern and/or impact on cardiac relaxation in health and disease, with a focus on how mechanical activity is regulated by physiological regulation using frequency-, length, and beta-adrenergic stimulation. A second area of interest is striated muscle function in muscular dystrophies, with a focus on treating cardiac dysfunction using drugs and gene therapy. Other projects include impact of hydroxyl radical damage on the myocardium, load dependent hypertrophy, and cardiopharmacology.
We use a wide variety of techniques to study myocardial relaxation, from the single cell level to the intact heart. Our main preparation is the multicellular trabeculae. These ultra-thin muscles (about 100 µm in diameter), possess all major cardiac cell types, and it's contractile behavior very closely mimics that of the whole heart. In such cardiac tissue, we can measure intracellular calcium transients, as well as changes in pH, under physiological temperature and frequency, in a variety of species, and we can keep these intact beating trabeculae alive and beating for several days. In addition, using confocal and 2-photon imaging, we are able to study myocyte dimensions under intact conditions. We have several models of disease, including pulmonary artery banding, and aortic banding. In collaborative studies, we assess skeletal muscle function (EDL and diaphragm) under a variety of conditions. For several studies, we use human cardiac tissue obtained after cardiac transplant surgery. Other techniques used are single cell mechanics, skinned fiber measurements, ECG and blood pressure measurements.
We have active collaborations within our department (Dr. Periasamy, Dr. Davis, Dr. Billman, Dr. Ziolo, Dr. Gyorke, Dr. Biesiadecki), as well as with labs in other departments (Dr. Rafael-Fortney, Dr. Carnes, Dr. Guttridge, Dr. Beattie) as well with investigators at Nationwide Childrens Hospital (Dr. Mendell, Dr. Martin, Dr. Kaspar, Dr. Montanaro, Dr. Rodino-Klapac).
Selection of Recent Publications (2011-2013):
• Xu Y, Delfín DA, Rafael-Fortney JA, Janssen PML. Lengthening-contractions in isolated myocardium impact force development and worsen cardiac contractile function in the mdx mouse model of muscular dystrophy. J Appl Physiol, 2011;110:512-519.
• Peterson JM, Kline W, Canan BD, Ricca DJ, Kaspar B, Delfín DA, DiRienzo K, Clemens PR, Robbins PD,Baldwin AS, Flood P, Kaumaya P, Freitas M, Kornegay JN, Mendell JR, Rafael-Fortney JA, Guttridge DC, Janssen PML. Peptide-based inhibition of NF-κB rescues diaphragm muscle contractile dysfunction in a murine model of Duchenne muscular dystrophy. Mol Med, 2011;17:508-515.
• Haizlip KM, Janssen PML. In vitro studies of early cardiac remodeling: impact on contraction and calcium handling. Frontiers in Bioscience, 2011:3:1047-1057.
• Delfín DA, Xu Y, Peterson JM, Guttridge DC, Rafael-Fortney JA, Janssen PML. Improvement of cardiac contractile function by peptide-based inhibition of NF-kappaB in the utrophin/dystrophin-deficient murine model of muscular dystrophy. J Transl Med 2011, 9:68.
• Roof SR, Shannon TR, Janssen PML*, Ziolo MT*. Effects of increased systolic Ca2+ d phospholamban phosphorylation during β-adrenergic stimulation on Ca2+ transient kinetics in cardiac myocytes. Am J Physiol Heart Circ Physiol, 2011;124:582-588, *contributed equally.
• Rafael-Fortney JA*, Chimanji NS, Schill KE, Martin CD, Murray JD, Ganguly R, Stangland JE, Tran T, Xu Y, Canan BD, Mays TA, Delfín DA, Janssen PML*, Raman SV*. Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice. Circulation 2011;124-582-588. *contributed equally.
• Xu Y, Monasky MM, Hiranandani N, Haizlip KM, Billman GE, Janssen PML. Effect of twitch interval duration on the contractile function of subsequent twitches in isolated rat, rabbit, and dog myocardium under physiological conditions. J Appl Physiol, 2011;111:1159-1167.
• Beastrom N, Lu H, Macke A, Canan BD, Johnson EK, Penton CM, Kaspar BK, Rodino-Klapac LR, Zhou L, Janssen PML, Montanaro F. Mdx5cv mice manifest more severe muscle dysfunction and diaphragm force deficits than mdx mice. Am J Pathology, 2011;179:2464-2474.
• Torres CAA, Janssen PML. Contractile strength during variable heart duration is species and pre-load dependent. J Biomed Biotech, 2011;294204.
• Bakkar N, Ladner K, Canan BD, Liyanarachchi S, Bal NC, Pant M, Periasamy M, Li Q, Janssen PML, Guttridge DC. IKKα and Alternative NF-κB Regulate PGC-1β to Promote Oxidative Muscle Metabolism J Cell Biol. 2012;196:497-511.
• Varian KD, Biesiadecki BJ, Ziolo MT, Davis JP, Janssen PML. Staurosporine Inhibits Frequency Dependent Myofilament Desensitization in Intact Rabbit Cardiac Trabeculae. Biochem. Res. Int., 2012;290971.
• Slabaugh JL, Brunello L, Gyorke S, Janssen PML. Contractile parameters and occurrence of alternans of isolated rat myocardium at supra-physiological stimulation frequency. Am J Physiol Heart Circ Physiol., 2012;302:2267-2275.
• Haizlip KM, Bupha-Intr T, Biesiadecki BJ, Janssen PML. Effects of increased preload on the force frequency response and contractile kinetics in early stages of cardiac muscle hypertrophy. Am J Physiol Heart Circ Physiol. 2012;302:H2509-2517.
• Delfín DA, Xu Y, Schill KE, Mays TA, Canan BD, Zang KE, Barnum JA, Janssen PML*, Rafael-Fortney JA*. Sustaining cardiac claudin-5 levels prevents functional hallmarks of cardiomyopathy in a muscular dystrophy mouse model. Mol Ther., 2012;20:1378-1383. *contributed equally.
• Delfín DA, Zang KE, Schill KE, Patel NT, Janssen PML, Rafael-Fortney JA. Cardiomyopathy in the dystrophin/utrophin-deficient mouse model of severe muscular dystrophy is characterized by dysregulation of matrix metalloproteinases. Neuromuscular Disorders. 2012;(in press).
• Grose WE, Clark KR, Griffin D, Malik V, Shontz KM, Montgomery CL, Lewis S, Brown Jr. RH, Janssen PML, Mendell JR and Rodino-Klapac LR. Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency Following AAV5 Gene Transfer. PLoS ONE 2012;7:e39233, 2012.
• Little SC, Biesiadecki BJ, Kilic A, Higgins RSD, Janssen PML, Davis JP. The rates of Ca2+ dissociation and cross-bridge detachment from ventricular myofibrils as reported by a fluorescent cardiac Troponin C. J Biol Chem. 2012;287:27930-27940.
• Haizlip KM, Hiranandani N, Biesiadecki BJ, Janssen PML. Impact of Hydroxyl Radical-Induced Injury on Calcium Handling and Myofilament sensitivity in Isolated Myocardium. J Appl. Physiol., 2012;113:766-774.
• Elnakish MT, Hassona MDH, Alhaj MA, Moldovan L, Janssen PML, Khan M, Hassanain HH. Rac-induced left ventricular dilation in thyroxin-treated ZmRacD transgenic mice: role of cardiomyocyte apoptosis and myocardial fibrosis. PLoS ONE, 2012;7:e42500.
• Bupha-Intr T, Haizlip KM, Janssen PML. Role of endothelin in the induction of cardiac hypertrophy in vitro. PLoS ONE, 2012;7:e43179.
• Roof SR, Biesiadecki BJ, Davis JP, Janssen PML, Ziolo MT. Effects of increased systolic Ca2+ and β-adrenergic stimulation on Ca2+ transient decline in NOS1 knockout cardiac myocytes. Nitric Oxide, 2012;27:242-247.
• Elnakish MT, Hassanain HH, Janssen PML. Vascular remodeling-associated hypertension leads to left ventricular hypertrophy and contractile dysfunction in profilin-1 transgenic mice. J. Cardiovasc. Pharmacol., 2012;60:544-552.
• Monasky MM, Taglieri DM, Jacobson AK, Haizlip KM, Solaro RJ, Janssen PML. Post-Translational Modifications of Myofilament Proteins Involved in Length-Dependent Prolongation of Relaxation in Rabbit Right Ventricular Myocardium. Arch Biochem Biophys. 2012 (in press).
• Murray JD, Canan BD, Martin CD, Stangland JE, Rastogi N, Rafael-Fortney JA, Janssen PML. The force-temperature relationship in healthy and dystrophic mouse diaphragm; implications for translational study design. Frontiers in striated muscle physiology. 2012;3:422.
• Kalyanasundaram A, Lacombe VA, Belevych A, Brunello L, Janssen PML, Kranias EG, Knollmann BC, Periasamy M, Gy?rke S. Upregulation of sarcoplasmic reticulum calcium uptake leads to heart failure and early mortality in mice deficient in expression of cardiac Calsequestrin. Cardiovasc. Res. 2012 (in press).
• Nixon BR, Liu B, Scellini B, Tesi C, Piroddi N, Ogut O, Solaro RJ, Ziolo MT, Janssen PML, Davis JP, Poggesi C, Biesiadecki BJ. Tropomyosin Ser-283 pseudo-phosphorylation slows myofibril relaxation. Arch Biochem Biophys. 2012 (in press). PMID: 23232082.
• Milani-Nejad N, Xu Y, Davis JP, Campbell KS, Janssen PML. Affect of muscle length on cross-bridge kinetics in intact cardiac trabeculae at body temperature. J Gen Physiol. 2013;141:133-139.
• Aeffner F, Abdulrahman B, Hickman-Davis JM, Janssen PML, Amer A, Bedwell DM, Sorscher EJ, Davis IC. Heterozygosity for the F508del mutation in the cystic fibrosis transmembrane conductance regulator anion channel attenuates influenza severity. J Infect Dis. 2013 (in press).
• Heller KN, Montgomery CL, Janssen PML, Clark KR, Mendell JR, Rodino-Klapac LR. AAV-mediated Overexpression of Human α 7 Integrin Leads to Histological and Functional Improvement in Dystrophic Mice. Molecular Ther. 2013 (in press).
• 08/15/2012-06/31/2016, Janssen (PI)
Frequency-dependent modulation of cardiac myofilament function in health/disease.
NIH RO1 HL113084.
• 09/01/2012-08/31/2015, Martin (PI), Janssen (Site-PI, Co-I)
Translational studies of GALGT2 gene therapy for Duchenne muscular dystrophy.
Army Medical Res & Materiel Command/DOD
• 08/01/2010-06/30/2015, Davis (PI), Janssen (Co-I)
Role of Cardiac Troponin in Health and Disease.
• 04/01/2012-03/31/2017, Guttrdige (PI), Janssen (Co-I)
NF-kB/IKK signaling in myogenesis and disease.
NIH R01 AR052787
• 04/15/2012-02/29/2017, Gyorke (PI), Janssen (Co-I)
Abnormal intracellular calcium release in heart failure.
NIH R01 HL074045
• 12/1/2010-11/30/2015, Beattie (PD), Janssen (Core-D PI)
Ohio State Neuroscience Core Grant
NIH NINDS P30 NS045758-06
• 07/01/2012-06/30/2014, Milani-Nejad (Student-PI), Janssen (Mentor)
Regulation of Cardiac Cross-Bridge Cycling Rate via Length-Dependent Post-Translational Modifications in Health/Disease
American Heart Association Predoctoral Fellowship 12PRE11480008