Update Your ProfileAcademic Title:
Professor
Primary Appointment:
Pharmacology & Physiology
Administrative Title:
Director, Center for Biomedical Engineering & Technology
Additional Title:
Director
Email:
Location:
BioMET Building, 111 S. Penn Street, Suite 104
Phone (Primary):
410-706-8181
Fax:
410-510-1545
Education and Training
- Harvard University, BA, Biochemistry, Magna Cum Laude, 1970
- Yale University, PhD, Physiology, 1975
- Yale University, MD, 1976
- University of Washington, Internship, Medicine, 1976 – 1977
- Oxford University, British-American Heart Fellowship, Physiology, 1977 – 1979
Biosketch
As a principal investigator for over 35 years, Dr. Lederer has led his team to several key discoveries in calcium signaling, including the 1992 discovery of calcium sparks, the calcium signals in the heart that underlie all heart contractions, as well as all other muscles and excitable cells. Dr. Lederer’s discovery and subsequent study of calcium sparks has led to the development of a new area of research in local signaling events.
Earlier in his career, while studying at Yale, Dr. Lederer discovered and characterized the transient inward current, a finding that contributed to medicine’s understanding of the arrhythmogenic delayed after-depolarization (DAD) and early after-depolarization (EAD) events. He also pioneered the use of confocal imaging in cardiac research, developing a number of techniques and tools. He is a leader in developing and implementing novel imaging technologies relevant to muscle biology that capture real-time signals at a high temporal and spatial resolution.
Recent discoveries include a new calcium-dependent, mechano-chemical signaling pathway called X-ROS, which links calcium signaling to the cytoskeleton and contraction. Dr. Lederer is Professor of Physiology in the School of Medicine and Director of the Center for Biomedical Engineering and Technology.
Research/Clinical Keywords
Calcium Signaling, Calcium Sparks, Calcium-Dependent Arrhythmogenesis, Excitation-Contraction (EC) Coupling, Sodium Calcium Exchange Mechanisms, , X-ROS Signaling, , Cardiac Hypertrophy, Heart Failure, Cardiac Myocytes, Cardiac Mitochondria, Cardiac Cellular Physiology, Computational Biology, Super-Resolution Imaging, Confocal Imaging
Highlighted Publications
Brandenburg, S., Kohl, T., Williams, G.S., Gusev, K., Wagner, E., Rog-Zielinska, E.A., Hebisch, E., Dura, M., Didié, M., Gotthardt, M., Nikolaev, V.O., Hasenfuss, G., Kohl, P., Ward, C.W., Lederer, W.J., Lehnart, S.E. (2016) Axial tubule junctions control rapid calcium signaling in atria. Journal of Clinical Investigations. 126,3999-4015. PMC5096811
Lin, Q., Zhao, G., Fang, X., Peng, X., Tang, H., Wang, H., Jing, R., Liu, J., Lederer, W.J., Chen, J., Ouyang, K. 2016. IP3 receptors regulate vascular smooth muscle contractility and hypertension, JCI Insight 1, e89402. PMC5070959
Brandenburg, S., Kohl, T., Williams, G.S., Gusev, K., Wagner, E., Rog-Zielinska, E.A., Hebisch, E., Dura, M., Didié, M., Gotthardt, M., Nikolaev, V.O., Hasenfuss, G., Kohl, P., Ward, C.W., Lederer, W.J., Lehnart, S.E. (2016) Axial tubule junctions control rapid calcium signaling in atria. Journal of Clinical Investigations. 2016 Sep 19. [Epub ahead of print]
Zhao, G., Li, T., Brochet, D.X., Rosenberg, P.B., Lederer, W.J. (2015) STIM1 enhances SR Ca2+ content through binding phospholamban in rat ventricular myocytes. Proceedings of the National Academy of Sciences USA. 112(34), E4792-801. PMC4553828
Previs, M.J., Prosser, B.L., Mun, J.Y., Previs, S. B., Gulick, J., Lee, K., Robbins, J., Craig, R., Lederer, W.J., Warshaw, D.M. (2015) Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling. Science Advances 1, e100205. PMC4380226
Greiser, M., Kerfant, B.G., Williams, G.S., Voigt, N., Harks, E., Dibb, K.M., Giese, A., Meszaros, J., Verheule, S., Ravens, U., Allessie, M.A., Gammie, J.S., van der Velden, J., Lederer, W.J., Dobrev, D., Schotten, U. (2014) Tachycardia-induced silencing of subcellular Ca2+ signaling in atrial myocytes. Journal of Clinical Investigations 124, 4759-72. PMC4347234
Additional Publication Citations
Dr. Lederer’s full list of publications can be found at: http://www.ncbi.nlm.nih.gov/myncbi/collections/bibliography/47162555/
Niggli, E., Lederer, W.J. (1990). Voltage-independent calcium release in heart muscle. Science. 250:565-568.
Gómez, A.M., Valdivia, H.H., Cheng, H., Lederer, M., Santana, L.F., Cannell, M.B., McCune, S.A., Altschuld, R.A. & Lederer, W.J. (1997) Defective excitation-contraction coupling in experimental cardiac hypertrophy and heart failure. Science 276, 800-806. Free article: http://www.sciencemag.org/content/276/5313/800.long
Lederer, W.J., Niggli, E. & Hadley, R.W. (1990) Sodium-calcium exchange in excitable cells: fuzzy space. Perspective article in Science 248, 283.
Cheng, H., Lederer, W.J., Cannell, M.B. (1993). Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262:740-744.
Klein, M.G., Cheng, H., Santana, L.F., Jiang, Y.-H., Lederer, W.J. & Schneider, M.F. (1996) Two mechanisms of quantized calcium release in skeletal muscle. Nature 379, 455-458.
Nelson, M.T., Cheng, H., Rubart, M., Santana, L.F., Bonev, A., Knot, H., Lederer, W.J. (1995) Relaxation of arterial smooth muscle by calcium sparks. Science 270:633-637.
Cheng, H., Lederer, W.J. (2008) Calcium Sparks. Physiol. Rev. 88,1491–1545. Free article: http://physrev.physiology.org/content/88/4/1491.long
Brochet, D.X.P., Yang, D., Di Maio, A., Lederer, W.J., Franzini-Armstrong, C., Cheng, H. (2005) Ca2+ blinks: Rapid nanoscopic store calcium signaling. PNAS102, 3099–3104. PMCID: PMC548797
Brochet, D.X.P., Xie,,W., Yang, D., Cheng, H., Lederer, W.J. (2011) Quarky Calcium Release in the Heart. Circ. Res. 108:210-218 PMCID: PMC3036985
Lederer, W.J. & Tsien, R.W. (1976) Transient inward current underlying arrhythmogenic effects of cardiotonic steroids in Purkinje fibres. J. Physiol. 263, 73 100. PMCID: PMC1307691
Mohler, P.J., Schott, J.-J., Gramolini, A.O., Dilly, K.W., Guatimosim, S., duBell, W.H., Song, L.-S., Haurogné, K., Kyndt, F., Ali, M.E., Rogers, T.B., Lederer, W.J., Escande, D., Le Marec, H. & Bennett, V. (2003) Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421, 634-9.
Wehrens, X.H.T., Lehnart, S.E., Huang, F., Vest, J.A., Reiken, S.R., Mohler, P.J., Sun, J., Guatimosim, S., Song, L.S., Rosemblit, N., D'Armiento, J.M., Napolitano, C., Memmi, M., Priori, S.G., Lederer, W.J. & Marks, A.R. (2003) FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 113, 829-840.
Song, L.S, Sobie, E.A., McCulle, S., Lederer, W.J., Balke, C.W., Cheng, H. (2006) Orphaned ryanodine receptors in the failing heart. PNAS 103, 4305-4310. PMCID: PMC1449688
Lehnart, S.E., Mongillo, M., Bellinger, A., Lindegger, N., Chen, B.X., Hsueh, W., Reiken, S., Wronska, A., Drew, L.J., Ward, C.W., Lederer, W.J., Kass, R.S., Morley, G., Marks, A.R. (2008) Leaky Ca release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice. J. Clin. Invest. 18, 2230-2245. PMCID: PMC2381750
Iribe, G., Ward, C.W., Camelliti, P., Bollensdorff, C., Mason, F., Burton, R.A., Garny, A., Morphew, M.K., Hoenger, A., Lederer, W.J., Kohl, P. (2009) Axial Stretch of Rat Single Ventricular Cardiomyocytes Causes an Acute and Transient Increase in Ca2+ Spark Rate. Circ. Res. 104, 787-95 PMCID: PMC3522525
Prosser, B.L., Ward, C.W., Lederer, W.J. (2011) “X-ROS signaling: Rapid mechano-chemo transduction in heart.” Science, 333(6048), 1440-5. PMCID: PMC3633162
Khairallah, R.J., Shi, G., Sbrana, F., Prosser, B. L., Borroto, C., Mazaitis, M.J., Hoffman, E.P., Mahurkar, A., Sachs, F., Sun, Y., Chen, Y.-W., Raiteri, R., Lederer, W.J., Dorsey, S. G., Ward, C. W. 2012. “Microtubules Underlie Dysfunction in Duchenne Muscular Dystrophy.” Science Signaling 5, ra56. PMCID: PMC3835660
Ward, C.W., Prosser, B.L., Lederer, W.J. (2014) Mechanical stretch induced activation of ROS/RNS signaling in striated muscle. Antioxidative Redox Signaling 20, 929-36. PMCID: PMC3924793
Williams, G.S., Chikando, A.C., Tuan, H.T., Sobie, E.A., Lederer, W.J., Jafri, M.S. (2011) Dynamics of Calcium Sparks and Calcium Leak in the Heart. Biophy. J. 101(6),1287-1296. PMCID: PMC3177068
Walker, M.A., Williams, G.S., Kohl, T., Lehnart, S.E., Jafri, M.S., Greenstein, J.L., Lederer, W.J., Winslow, R.L. (2014) Superresolution modeling of calcium release in the heart. Biophy. J. 107, 3009-20. PMCID: PMC4269784
Boyman, L., Williams, G.S., Khananshvili, D., Sekler, I., Lederer, W.J. (2013) NCLX: The mitochondrial sodium calcium exchanger. J. Mol. Cell. Cardiol. 59:205-13. PMCID: PMC3951392
Williams, G.S., Boyman, L., Chikando, A.C., Khairallah, R.J., Lederer, W.J. (2013) Mitochondrial calcium uptake. PNAS, U S A. 110, 10479-86. PMCID: PMC3177068
Boyman, L., Chikando, A.C., Williams, G.S., Khairallah, R.J., Kettlewell, S., Ward, C.W., Smith, G.L., Kao, J.P., Lederer, W.J. (2014) Calcium movement in cardiac mitochondria. Biophys. J. 107, 1289-301. PMCID: PMC3951392
Research Interests
Publications cited below can be found in the additional publication section.
Excitation-contraction (EC) coupling in heart and the molecular and cellular basis of Ca2+ signaling: the central role of local Ca2+ signaling. Dr. Lederer, along with an international set of collaborators, have defined the central role of local Ca2+ signaling in excitation-contraction (EC) coupling in heart and the molecular and cellular basis of Ca2+ signaling in excitable cells. Until the discoveries by the Lederer team, there was only modest evidence demonstrating the central role of nanoscopic (molecular, subcellular) Ca2+signaling in EC coupling. Niggli and Lederer 1990 showed that the voltage dependence of the [Ca2+]i signal provides critical information regarding the spatial organization of the EC coupling machinery. Gomez et al. 1997 extended the work to show that in cardiac hypertrophy and heart failure, EC coupling becomes defective. This work took on more significance with the discovery of local Ca2+ signaling and the discovery of Ca2+ sparks and blinks in cardiac, skeletal and smooth muscle.
Local Ca2+ signaling and the discovery of Ca2+ sparks and blinks in cardiac, skeletal and smooth muscle. The discovery and characterization by the Lederer team (including Drs. Mark Cannell and Heping Cheng) revolutionized our understanding of Ca2+ signaling in cardiac (Cheng et al. 1993), skeletal (Klein et al. 1996) and smooth muscle (Nelson et al. 1995). The study of Ca2+ sparks (Cheng and Lederer 2008) and the reciprocal SR Ca2+ depletion signal, a Ca2+ blink, (Brochet et al. 2005) in heart provided a new mechanistic view of EC coupling, Ca2+ dependent arrhythmogenesis and signaling rules for both the sarcoplasmic reticulum (SR) and other sarcolemma. These Ca2+ release events arise from the coordinated signaling of a cluster of SR Ca2+ release channels (RyRs). Ca2+ release events that could arise from single RyRs (calcium quarks) had been shown to occur in modeling experiments or in vitro in bilayer experiments, but were demonstrated in vivo by the Lederer group (Brochet et al. 2011).
Ca2+ dependent arrhythmogenesis. Studying normal calcium signaling has led Dr. Lederer and his colleagues to discoveries of the role of calcium in the development of calcium dependent arrhythmias. How Ca2+ signaling dysfunction and SR Ca2+ overload could lead to arrhythmogenesis was first articulated in Lederer and Tsien 1976, with many follow-up papers by Lederer and other investigators. Similar Ca2+ -dependent arrhythmias were shown to arise from mutations in the cytoskeleton (Mohler et al. 2003), mutations in RyR (Wehrens et al. 2003) in heart failure (Song et al. 2006) and in catecholaminergic polymorphic ventricular tachycardia (Lehnart et al. 2008), both in common and rare pathologies.
Chemo-mechanical signaling in muscle: X-ROS signaling in heart and skeletal muscle. The most recent discoveries link calcium to the contraction machinery. Lederer and his colleagues discovered a new signaling pathway, X-ROS signaling, when studying how mechanical changes in single heart cells can affect Ca2+ signaling (Iribe et al. 2009) with normal physiological and unusual pathological consequences (Prosser et al. 2011). This signaling pathway arises as the mechanical changes in the heart cell shape distort the cellular cytoskeleton (microtubules) which can activate NADPH-oxidase to generate local (subcellular) reactive oxygen species (mainly H2O2). This reactive oxygen reversibly oxidizes diverse targets including RyR and many other targets to increase the rate of SR Ca2+ release and Ca2+ sparks. This is an area of exploding active research in which Lederer and colleagues are very active participants (Khairallah et al. 2012; Ward et al. 2014).
Computational biology: modeling Ca2+ signaling at high temporal and spatial resolution in cardiac myocytes and in cardiac mitochondria. The most recent work in the Lederer laboratory combines computational biology with high resolution imaging and electrophysiology by modeling Ca2+ signaling at high temporal and spatial resolution in cardiac myocytes and in cardiac mitochondria. When results are organized quantitatively and mechanistically, mathematical modeling or simulations of the experimental findings have rich value. Lederer, his trainees and his colleagues have sought to organize their findings quantitatively as an extension of the experiments. Williams et al. 2011 and Walker et al. 2014 examine Ca2+ sparks, Ca2+ quarks, and [Ca2+]i transients at the cellular and subcellular levels at high temporal and spatial resolution. Boyman et al. 2013, Williams et al. 2013 and Boyman et al. 2014 examine Ca2+ movement in mitochondria.
Awards and Affiliations
Affiliations:
- 1979-1983: Assistant Professor of Physiology, University of Maryland School of Medicine
- 1983-1988: Associate Professor of Physiology (with tenure), University of Maryland School of Medicine
- 1988-present: Professor of Physiology, University of Maryland School of Medicine
- 1995-2009: Professor, Medical Biotechnology Center, University of Maryland Biotechnology Institute
- 1995-present: Adjunct Professor, Department of Pharmacology, University of Vermont
- 2000: Awarded Tenure, MBC, UMBI
- 2009-present: Guest Professor, Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University
- 2010-present: Adjunct Research Scientist, Institute of Computational Medicine, Whiting School of Engineering, The Johns Hopkins University
- 2015-present: Affiliate Professor, Department of Bioengineering, University of Maryland College Park
Awards:
- 1977-1979: British Heart Foundation ‑ American Heart Association Fellowship
- 1981-1986: Established Investigator of the American Heart Association
- 1982-present: American Men and Women of Science
- 1993-1997: Councilor, Biophysical Society
- 1993-2003: NIH Merit Award
- 1994: Peter Dresler Memorial Lectureship, Dalhousie University School of Medicine
- 1995: Wellcome Lecturer, Loyola University School of Medicine, Chicago, IL
- 1997: National Lecturer: Korean Physiological Society, Seoul, Korea.
- 1998: Cole Award, Biophysical Society
- 1999: Regents Faculty Award for Excellence in Research, University System of Maryland
- 1999: Wellcome Lecturer, University of Mississippi School of Medicine, Jackson, MS
- 2001: Founding Fellow, International Society for Heart Research
- 2002: Fellow of the Biophysical Society
- 2002: D’Agrosa Lecturer, St. Louis University, St. Louis, MO
- 2007: 9th Annual Fred Fay Lecturer, University of Massachusetts School of Medicine
- 2007: 18th Annual Gordon Moe Lecturer, Cardiac Electrophysiology Society Annual Meeting
- 2008: Isaac Starr Lecture, Cardiac Systems Dynamics Society
- 2008: Fellow of the American Heart Association
- 2012: Kirby Lecture, Temple University
- 2012: Stern Lecture, Mount Sinai School of Medicine, NY, NY
- 2012: Plenary Lecture, International Chair of Therapeutic Innovation, University of Paris
- 2012: Paul Horowicz Lecture, University of Rochester Medical Center
- 2012: Lamport Lecture, University of Washington
- 2013: The Dirk L. Brutsaert Lecture, European Society for Cardiology
- 2013: UMB Researcher of the Year
- 2014: Cairns Research Keynote Speaker, Northern Cardiovascular Research Group
- 2015: Peter Harris Distinguished Scientist Award, International Society for Heart Research
- 2015: Keynote Speaker, Asian Biophysical Association Annual Meeting
- 2016; Keynote Speaker, Physiological Society Annual Meeting
- 2016: Honorary Member, Physiological Society