Cornell University, B.S. in Applied & Engr. Physics
University of Rochester School of Medicine and Dentistry, M.S. in Biophysics
University of Rochester School of Medicine and Dentistry, Ph.D. in Biophysics
Research Interests – Arrhythmias, Cardiomyopathy and Heart Failure, Glycan and Ion Transport Regulation in Health and Disease
Our lab is broadly interested in understanding the control, modulation and pathophysiology of electrical signaling and how altered electrical signaling contributes to cardiac, neuronal and skeletal muscle diseases such as arrhythmias, epilepsies, and myopathies. Specifically, we are interested in describing the physiological and pathophysiological mechanisms by which posttranslational modifications, specifically glycosylation, alters transmembrane protein function and how these glyco-dependent changes in protein function impact electromechanical signaling and overall cardiac, brain, and skeletal muscle function.
Current, ongoing project include:
1. We are investigating whether and how glycosylation and its regulation directly modulate cardiac voltage-gated ion channel (VGIC) gating that leads to changes in cardiac excitability and conduction, and how changes in glycosylation that are known to occur in humans contribute to a pro-arrhythmogenic state.
2. Our recent data suggest that regulated glycosylation contributes to both electrical and contractile dysfunction in the heart. Thus, we are also investigating how altered glycosylation impacts cardiac electromechanical activity at all levels ranging from the ion channels and contractile proteins responsible for electromechanical cellular processes through contraction and relaxation of the whole heart.
3. We also have shown that neuronal function is directly affected by altered glycosylation and are investigating how such changes in glycosylation contribute to altered neuronal excitability and/or conduction.
4. We collaborate very closely with Dr. Hui Yang, Associate Professor, Harold and Inge Marcus Department of Industrial and Manufacturing Engineering, The Pennsylvania State University (http://www.personal.psu.edu/huy25/), to develop and validate mathematical/statistical models that describe and predict cardiac function across all scales, from the ion channel through the whole heart.
Many of our studies involve a range of in vitro, ex vivo, in vivo, and in-silico experiments on conditional mouse knockout strains that serve as a model for physiological and/or pathologic changes in protein glycosylation. Techniques used include ECG and echocardiographic measurements, optical mapping of voltage and Ca2+ waves across the epicardium, primary/immortal cell culture methods, ion channel electrophysiological studies, histology, Ca2+ handling and cellular contractility measurements, Ca2+ spark measurements, action potential measurements, and protein/glycan biochemistry using a combination of purification methods, gel electrophoresis, lectin biology, immunocytochemistry, basic confocal microscopy, and molecular biology.
W. Deng, A. R. Ednie, J. Qi, and E.S. Bennett. Aberrant Sialylation Causes Dilated Cardiomyopathy and Stress-induced Heart Failure. Basic Research in Cardiology, 2016 September, 111:57. PMID: 27506532; DOI:10.1007/s00395-016-0574-1. http://link.springer.com/article/10.1007%2Fs00395-016-0574-1
A.R. Ednie and E.S. Bennett. Reduced Sialylation Impacts Ventricular Repolarization by Modulating Specific K+ Channel Isoforms Distinctly. J Biol Chem. 2015 Jan 30;290(5):2769-83. http://www.jbc.org/content/290/5/2769.long
A.R. Ednie, J. M. Harper, and E.S. Bennett. Sialic Acids Attached to N- and O-glycans Within the Nav1.4 D1S5-S6 Linker Contribute to Channel Gating. Biochimica et Biophysica Acta, General Subjects 1850 (2015) 307–317. http://www.sciencedirect.com/science/article/pii/S0304416514003638
A.R. Ednie, K.K. Horton, J Wu, and E.S. Bennett. Expression of the sialyltransferase, ST3Gal4, impacts cardiac voltage-gated sodium channel activity, refractory period and ventricular conduction. Journal of Molecular and Cellular Cardiology 59 (2013) 117–127. PMID: 23471032. https://doi.org/10.1016/j.yjmcc.2013.02.013.
D. Du, H. Yang, A. Ednie, and E. S. Bennett. In-silico modeling of the functional role of reduced sialylation in sodium and potassium channel gating of mouse ventricular myocytes. IEEE Journal of Biomedical and Health Informatics, 2017. DOI: 10.1109/JBHI.2017.2664579
D. Du, H. Yang, A. Ednie, and E.S. Bennett. Statistical metamodeling and sequential design of computer experiments to model glyco-altered gating of sodium channels in cardiac myocytes. IEEE J. Biomedical and health informatics, Vol. 20, No. 5, Sept., 2016. DOI: 10.1109/JBHI.2015.2458791.
D. Du*, H. Yang, S. Norring, and E. Bennett, “In-silico modeling of glycosylation modulation dynamics in hERG channels and cardiac electrical signaling,” ,” IEEE J. of Biomedical and Health Informatics (Featured Article), Vol. 18, No. 1, 2013, PMID: 24403418 10.1109/JBHI.2013.2260864
S.A. Norring, A.R. Ednie, T.A. Schwetz, D. Du, H. Yang, E.S. Bennett. Channel sialic acids limit hERG channel activity during the ventricular action potential. FASEB J. 2013 Feb;27(2):622-31. doi: 10.1096/fj.12-214387. Epub 2012 Nov 8. PMID: 23139156. http://www.fasebj.org/content/27/2/622.full.pdf
T.A. Schwetz, S.A. Norring, A.R. Ednie, and E.S. Bennett. Sialic acids attached to O-glycans modulate voltage-gated potassium channel function. J Biol Chem. 2010 Nov 29. [Epub ahead of print] http://www.jbc.org/content/early/2010/11/29/jbc.M110.171322.full.pdf
T.A. Schwetz, S.A. Norring, and E.S. Bennett. N-glycans Modulate Kv1.5 Gating but have no effect on Kv1.4 gating. Biochimica et Biophysica Acta 1798 (2010) 367–375. doi:10.1016/j.bbamem.2009.11.018
M.L. Montpetit, P.J. Stocker, T.A. Schwetz, J.M. Harper, S.A. Norring, L. Schaffer, S.J. North, J. Jang-Lee, T. Gilmartin, S.R. Head, S.M. Haslam, A. Dell, J.D. Marth, E.S. Bennett. Regulated and aberrant glycosylation modulate cardiac electrical signaling, Proc. Natl. Acad. Sci. U. S. A 106(38), 16517-16522, 2009. http://www.pnas.org/content/106/38/16517.long.
(Feature article of the month, Functional Glycomics Gateway, Nature.com, September, 2009; Functional Glycomics, 10 Sept., 2009, doi:10.1038/fg.2009.29 http://www.functionalglycomics.org/fg/update/2009/090910/full/fg.2009.29.shtml
D. Johnson and E. S. Bennett. Gating of the shaker potassium channel is modulated differentially by N-glycosylation and sialic acids. Pflügers Archiv - European Journal of Physiology, 456, (2), 393-405.
D. Johnson and E. S. Bennett. Isoform-specific effects of the b2 subunit on voltage-gated sodium channel gating. J. Biol. Chem., 281(36), 25875-25881, 2006.
P.J. Stocker and E. S. Bennett. Differential Sialylation Modulates Voltage-Gated Na+ Channel Gating Throughout the Developing Myocardium. J. Gen. Physiol., 127 (3), 253-265, 2006.
D. Johnson, M.L. Montpetit, P. J. Stocker, and E.S. Bennett. The sialic acid component of the beta1 subunit modulates voltage-gated sodium channel function. J. Biol. Chem., 279, 44303-44310, 2004. http://www.jbc.org/cgi/content/full/279/43/44303
E.S. Bennett, B.E. Smith, and J. Harper. Voltage-gated Na+ channels confer invasive properties to human prostate cancer cells. Pflugers Arch – Eur. J. Physiol. 447: 908-914, 2004. http://www.springerlink.com/content/aqcq2egy0t4mpguh/
E.S. Bennett. Isoform-specific effects of sialic acid on voltage-dependent Na+ channel gating: Functional sialic acids are localized to the S5-S6 loop of domain I. J. Physiol., 538.3, 675-690, 2002. http://jp.physoc.org/cgi/content/full/538/3/675