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Department of Pharmacology

Department of Pharmacology

Colleen E. Clancy, Ph.D.

 
Colleen E. Clancy, Ph.D.

Professor
Ph.D., Case Western Reserve University, 2001
(530) 754-0254
e-mail

Research Interests

Computational approaches to reveal mechanisms of excitability in the heart and brain.

 

Research Synopsis

The Clancy Lab aims to develop and implement computational approaches to understand mechanisms of excitable disease in the heart and brain. Electrically based syndromes such as arrhythmia and epilepsy are integrative disorders that result in disruption of normal electrical behavior. In arrhythmia cardiac electrical synchrony is abolished, while epileptic seizures result from pathological synchronization in neuronal networks. However, understanding the precise cause of these syndromes has been extremely difficult. This may be due, in part, to inadequate approaches to understand system level electrical disorders that focus on one specific part of the system and fail to reveal the most valuable information—how protein and cell anomalies affect complex interactions to disrupt the tissue and cause the disease state. To achieve an integrative understanding of such a complex system we use mathematics and high performance computing to construct quantitative representations of the heart and hippocampus brain region. The general approach used in the laboratory is to design detailed models of ion channel activity that can be used to study perturbations, such as those caused by effects of drugs, mutations or phosphorylation. Ion channel models are then incorporated into virtual excitable cells and connected to form functional models of tissues, which allows us to follow perturbations across multiple scales, from the modified proteins to altered cellular states to the propagation of the perturbation in cell networks. We are also attempting to build predictive models of pharmacological intervention during arrhythmia. Prediction of the origin and pathway of pathological triggers, and strategies for intervention may ultimately lead to improved diagnosis and treatment..

 

Selected Publications

Clancy, C.E. and Rudy, Y. Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia. Nature. 1999: 400. 566-569.

Clancy, C.E. and Rudy, Y. Cellular consequences of HERG mutations in the Long QT Syndrome: Precursors to sudden cardiac death. Cardiovascular Research. 2001:50:2. 301-313.

Clancy, C.E. and Rudy, Y. A Na+ channel mutation that causes both Brugada and Long-QT syndrome phenotypes: A simulation study of mechanism. Circulation. 2002:105:1208-1213.

Liu, H., Tateyama, M., Clancy, C.E., Abriel, H. and Kass, R.S. Channel openings are necessary but not sufficient for use-dependent block of cardiac Na+ channels by flecainide: evidence from the analysis of disease-linked mutations. Journal of General Physiology. 2002. 120(1):39-51.

Splawski, I., Timothy, K., Tateyama, M. Clancy, C.E., Malhotra, A., Beggs,A., Cappuccio, F., Sagnella, G.A. Kass, R.S., and Keating, M.T. African sodium channel polymorphism implicated in sudden death from cardiac arrhythmias. Science. 2002:297:1333-1336.

Clancy, C.E., Tataeyama, M. and Kass, R.S. Novel insights into the molecular mechanisms of bradycardia-triggered arrhythmias in the Long QT-3 syndrome. Journal of Clinical Investigation. 2002:110:1251-1262.

Clancy, C.E., Tataeyama, M., Liu, H., Wehrens, X.H.T. and Kass, R.S. Non-equilibrium gating in Cardiac Na+ channels: An original mechanism of arrhythmia. Circulation (Rapid Track). 2003:107:2233-223.

Clancy, C.E. and R.S. Kass. “Theoretical investigation of the neuronal Na+ channel SCN1A: Abnormal gating and epilepsy.” Biophysical Journal. 2004. 86(4): 2606-14.

Terrenoire*, C., Clancy*, C.E., Cormier*, J.W., Sampson, K. and R.S. Kass. "Autonomic control of cardiac action potentials; Role of potassium channel kinetics in response to sympathetic stimulation”. Circulation Research (ultrarapid communication). 2005. 18;96(5):e25-3. *equal contribution

Clancy, C.E. and R.S. Kass. Invited review. “K+ and Na+ cardiac ion channel mutations: from DNA to ECG.” Physiological Reviews. 2005. 85: 33-47.

Clancy, C.E., Zhu, Z. I., and Rudy, Y. "Pharmacogenetics and anti-arrhythmic drug therapy: A theoretical investigation". American Journal of Physiology. 2007. Jan;292(1):H66-75.

Nakamura, H., Kurokawa, J., Bai, C-X., Asada, K., Oren, RV., Xu, J. Clancy, C.E., Isobe, M., Furukawa, T. " Progesterone regulates cardiac repolarization through a non-genomic pathway: in vitro patch-clamp study and cellular/multicellular computer modeling". Circulation. 2007. Dec 18;116(25):2913-22.

Xu, J. and Clancy, C.E. "Ionic Mechanisms of Bursting in CA3 Hippocampal Pyramidal Neurons: A Model Study". PLoS ONE. 2008. Apr 30;3(4):e2056.

Yang, P-C. and Clancy, C.E. "Insight into the mechanisms of gender susceptibility to cardiac arrhythmia: A multiscale study". PLoS, Computational Biology. 2010. 29;6(1):e10006582009.

Oren, R.V. and Clancy, C.E. "Determinants of heterogeneity, excitation and conduction in the sinoatrial node: A model study". PLoS, Computational Biology. 2010 Dec 23;6(12):e1001041.

Moreno, J.D., Zhu, Z.I., Yang, P.C., Bankston, J.R., Jeng, M.T., Kang, C., Wang, L., Bayer, J.D., Christini, D.J., Trayanova, N.A., Ripplinger, C. M., Kass, R.S., and Clancy, C.E. "A computational model to predict the effects of class I antiarrhythmic drugs on ventricular rhythms". Science Translational Medicine. 2011. Aug 31;3(98):98ra83.

See: Complete List of Publications

 

Selected Recent Honors

2010 Invited Moderator. Journal of Molecular and Cellular Cardiology podcast on, “The pathophysiological mechanism of the Brugada Syndrome”. November 2010, Journal of Molecular and Cellular Cardiology. http://www.elsevier.com/wps/find/L03.cws_home/podcast_brugada_syndrome 

2010 “What’s Gender Got to Do with It?” Article highlighting research in the Clancy Lab, Fall 2010. Go Red For Women newsletter from the American Heart Association.

2011 The poster (J.D. Moreno and C.E. Clancy) entitled ‘A multiscale model to predict antiarrhythmic drug effects on cardiac rhythms ' was selected as best poster in the young investigator competition at the Gordon research conference on Cardiac Arrhythmias.

2011 Featured in a Naked Scientists (award winning BBC weekly radio program) radiocast and article entitled, “Good News for Broken Hearts” (www.thenakedscientists.com) to discuss computer models of antiarrhythmic drugs. http://www.thenakedscientists.com/HTML/content/news-archive/news/2361/

2011 Feature article in Scientific American extreme tech section entitled, “Virtual Ventricle: Computer Predicts Dangers of Arrhythmia Drugs Better than Animal Testing”. September 1, 2011. http://www.scientificamerican.com/article.cfm?id=computer-heart-simulation-arrhythmia

2011 The article “Ionic mechanisms of endogenous bursting in CA3 hippocampal pyramidal neurons: a model study” by Xu and Clancy (PLoS One 2008), was selected and evaluated by the Faculty of 1000 (F1000).