Purkinje Cells and Arrhythmia Mechanisms

Summary

Principal Investigator: Glenn I Fishman
Abstract: DESCRIPTION (provided by applicant): PROJECT SUMMARY Heart disease remains the leading cause of death in the United States and other developed countries. Half of these deaths occur suddenly, typically from ventricular tachyarrhythmias that arise in the setting of acute ischemia, acquired heart disease or inherited syndromes including channelopathies and cardiomyopathies. The specialized cardiac conduction system (CCS) comprises a heterogeneous network of cells that orchestrate the initiation and propagation of a wave of electrical excitation throughout the myocardium. Purkinje cells comprise the most distal component of the CCS and substantial, but indirect experimental data has accumulated supporting the concept that Purkinje cells play a key mechanistic role triggering a broad range of life-threatening ventricular arrhythmias. However, major gaps in our understanding of Purkinje cell biology have prevented this realization from being translated into novel anti-arrhythmic strategies. Through our recent identification of contactin-2, a novel cell adhesion molecule expressed in the conduction system, we have established new tools to identify, isolate and characterize murine Purkinje cells. Using these tools, we propose a series of studies to investigate contactin-2 dependent regulation of Purkinje network development, the regulation of cardiac electrophysiology by contactin-2 in normal and diseased hearts, and contactin-2 dependent mechanisms regulating pathologic remodeling in Purkinje cells. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Heart disease is the leading cause of death in the United States and other developed countries and almost half of these deaths occur suddenly from heart rhythm abnormalities. Our research is directed toward understanding the mechanisms responsible for these lethal arrhythmias and identifying potential new therapeutic targets.
Funding Period: 2011-04-01 - 2015-11-30
more information: NIH RePORT

Top Publications

  1. pmc Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes
    Xianming Lin
    Leon H Charney Division of Cardiology, New York University School of Medicine, New York, New York 10016, USA
    Heart Rhythm 8:1923-30. 2011
  2. pmc Ankyrin-G participates in INa remodeling in myocytes from the border zones of infarcted canine heart
    Wen Dun
    Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, New York, United States of America
    PLoS ONE 8:e78087. 2013
  3. pmc GATA factors efficiently direct cardiac fate from embryonic stem cells
    Harma K Turbendian
    Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
    Development 140:1639-44. 2013
  4. pmc Designer gap junctions that prevent cardiac arrhythmias
    Eugene Kim
    Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA
    Trends Cardiovasc Med 23:33-8. 2013
  5. pmc Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype
    Stacey Rentschler
    Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104, USA
    Circulation 126:1058-66. 2012
  6. pmc Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models
    Benjamin F Remo
    Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, NY 10016, USA
    J Membr Biol 245:275-81. 2012
  7. pmc Unique properties of the ATP-sensitive K⁺ channel in the mouse ventricular cardiac conduction system
    Li Bao
    Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA
    Circ Arrhythm Electrophysiol 4:926-35. 2011

Research Grants

Detail Information

Publications11

  1. pmc Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes
    Xianming Lin
    Leon H Charney Division of Cardiology, New York University School of Medicine, New York, New York 10016, USA
    Heart Rhythm 8:1923-30. 2011
    ..Sodium channel α-subunits in ventricular myocytes (VMs) segregate either to the intercalated disc or to lateral membranes, where they associate with region-specific molecules...
  2. pmc Ankyrin-G participates in INa remodeling in myocytes from the border zones of infarcted canine heart
    Wen Dun
    Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, New York, United States of America
    PLoS ONE 8:e78087. 2013
    ..Gap and mechanical junctional proteins remodel in IZPCs early, perhaps to help maintain Nav1.5 subcellular location position and preserve its function soon after myocardial infarction. ..
  3. pmc GATA factors efficiently direct cardiac fate from embryonic stem cells
    Harma K Turbendian
    Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA
    Development 140:1639-44. 2013
    ..Thus, GATA factors can function in ESC derivatives upstream of other cardiac transcription factors to direct the efficient generation of cardiomyocytes...
  4. pmc Designer gap junctions that prevent cardiac arrhythmias
    Eugene Kim
    Leon H Charney Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA
    Trends Cardiovasc Med 23:33-8. 2013
    ..We also describe efforts to engineer "designer" gap junctions that are resistant to pathologic remodeling...
  5. pmc Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype
    Stacey Rentschler
    Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104, USA
    Circulation 126:1058-66. 2012
    ..We hypothesized that Notch may also be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells...
  6. pmc Connexin43 cardiac gap junction remodeling: lessons from genetically engineered murine models
    Benjamin F Remo
    Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, NY 10016, USA
    J Membr Biol 245:275-81. 2012
    ....
  7. pmc Unique properties of the ATP-sensitive K⁺ channel in the mouse ventricular cardiac conduction system
    Li Bao
    Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA
    Circ Arrhythm Electrophysiol 4:926-35. 2011
    ..Conclusions- These data imply a differential electrophysiological response (and possible contribution to arrhythmias) of the ventricular CCS to K(ATP) channel opening during periods of ischemia...

Research Grants30

  1. Azithromycin and Sudden Cardiac Death: Electrophysiologic Mechanisms
    Katherine T Murray; Fiscal Year: 2013
    ..Thus, an improved understanding of the basic mechanisms causing azithromycin-induced sudden cardiac death should lead to safer pharmacotherapy. ..
  2. Calcium Entrained Arrhythmias
    RAIMOND LESTER WINSLOW; Fiscal Year: 2013
    ..The proposed work will provide new understanding of the molecular and cellular causes of these heart rhythm disturbances and enable new treatments. ..
  3. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  4. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  5. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  6. Mechanisms of Adaptation to Exercise in Health and COPD
    Peter D Wagner; Fiscal Year: 2013
    ....