Cell-type Specificity of Heritable Channelopathies: Role of the Purkinje Fiber

Summary

Principal Investigator: Vivek Iyer
Abstract: DESCRIPTION (provided by applicant): This proposal details a comprehensive 5-year training program for my career development in cardiovascular research. This plan is designed to provide the additional scientific and technical training that will prepare me for an independent career in academic research. With the support provided by this grant, I will seek additional formal training in ion channel biophysics and the mathematical sciences and further my technical expertise with patch clamp techniques and in vitro analysis of cellular electrophysiology. Sudden cardiac death claims the lives of 350,000 Americans each year (equivalent to 1000 people a day or one person every two minutes). Many of these events occur as a consequence of inherited arrhythmias that cause dysfunction of ion channels, or "channelopathies." The central hypothesis of this proposal is that the cardiac specialized conduction system, comprised of Purkinje fiber (PF) cells, plays a central role in the formation and maintenance of these deadly arrhythmias. In this proposal, the Purkinje system will be studied in a combined in vitro and computational approach in order to examine a novel paradigm: whether differences in tissue type and their interplay modulate the cellular effect of heritable channelopathies. The findings promise to have important implications in the pharmacologic management of affected patients. The insight gained may also enhance our understanding of channel dysfunction in more widespread cardiovascular conditions, such as heart failure and ischemia. My aims are: 1. To investigate how changes in cell type regulate channel dysfunction in single/isolated Purkinje fiber (PF) cells and ventricular myocyte (VM) cells. 2. To study the cellular triggers of arrhythmi in channelopathy using an experimental mouse model, alongside the corresponding computational model. 3. To utilize multidimensional simulation to determine the impact of mutations in the Purkinje fiber system and interplay with the ventricle, establishing a link between genetic lesion and arrhythmia on the whole organ level.
Funding Period: 2013-08-19 - 2018-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Catheter ablation for ventricular tachyarrhythmias in patients supported by continuous-flow left ventricular assist devices
    Arthur R Garan
    From the Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York and Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York
    ASAIO J 60:311-6. 2014
  2. pmc Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber
    Vivek Iyer
    Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America
    PLoS ONE 9:e97720. 2014

Research Grants

  1. Endophenotypes of Sleep Apnea and Role of Obesity
    ALLAN IAN PACK; Fiscal Year: 2013
  2. Cardiac Ion Channel Regulation
    Isabelle Deschenes; Fiscal Year: 2013
  3. Novel Therapies for Muco-Obstructive Lung Diseases
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
  4. CaMKII and InsP3-Mediated Signaling in Cardiac Myocytes
    Donald M Bers; Fiscal Year: 2013
  5. Molecular motors in cell biology
    Yale E Goldman; Fiscal Year: 2013
  6. Caveolae and Cardiac Repolarization
    TIMOTHY KAMP; Fiscal Year: 2013
  7. Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury
    Asrar B Malik; Fiscal Year: 2013
  8. Regulation of the Cardiac Sodium Channel by SIRTUIN1
    Barry London; Fiscal Year: 2013
  9. Molecular Mechanisms of Stretch-Induced Electrical Remodeling in the Heart
    ANDREAS AUGUSTINUS WERDICH; Fiscal Year: 2013
  10. K+ Channel Trafficking and Modulation by Mink and MiRP1
    Geoffrey W Abbott; Fiscal Year: 2013

Detail Information

Publications4

  1. ncbi Catheter ablation for ventricular tachyarrhythmias in patients supported by continuous-flow left ventricular assist devices
    Arthur R Garan
    From the Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York and Department of Surgery, Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York
    ASAIO J 60:311-6. 2014
    ..7%). One patient (14.3%) experienced a bleeding complication after the procedure. For patients with a high VA burden after LVAD implantation, VT ablation is safe and feasible, but VA frequently recurs. ..
  2. pmc Modeling tissue- and mutation- specific electrophysiological effects in the long QT syndrome: role of the Purkinje fiber
    Vivek Iyer
    Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York, United States of America
    PLoS ONE 9:e97720. 2014
    ..The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies. ..

Research Grants31

  1. Endophenotypes of Sleep Apnea and Role of Obesity
    ALLAN IAN PACK; Fiscal Year: 2013
    ..It will lead to a new molecular signature of OSA that could transform the practice of medicine in this area in a new, cost-effective way. ..
  2. Cardiac Ion Channel Regulation
    Isabelle Deschenes; Fiscal Year: 2013
    ....
  3. Novel Therapies for Muco-Obstructive Lung Diseases
    RICHARD CHARLES BOUCHER; Fiscal Year: 2013
    ..abstract_text> ..
  4. CaMKII and InsP3-Mediated Signaling in Cardiac Myocytes
    Donald M Bers; Fiscal Year: 2013
    ..Results will greatly increase our understanding of the roles of CaMKll and InsP3R in cardiac myocytes during ECC, arrhythmogenesis &nuclear signaling in normal, Hyp and HF cardiac myocytes. ..
  5. Molecular motors in cell biology
    Yale E Goldman; Fiscal Year: 2013
    ..We anticipate that the proposed work will take us significantly further toward our goal of understanding motility in the normal and pathological function of cells. ..
  6. Caveolae and Cardiac Repolarization
    TIMOTHY KAMP; Fiscal Year: 2013
    ..These studies will provide mechanistic new insights into the control of cardiac repolarization and abnormalities in disease which can result in arrhythmias. ..
  7. Mechanisms of PMN and Endothelial-Mediated Lung Inflammation and Injury
    Asrar B Malik; Fiscal Year: 2013
    ..abstract_text> ..
  8. Regulation of the Cardiac Sodium Channel by SIRTUIN1
    Barry London; Fiscal Year: 2013
    ..In doing so, it will open the door for pharmacologic SIRT1 activators as potential therapeutic agents in patients at risk for cardiac arrhythmias dues to inherited and acquired disturbances in cardiac INa. ..
  9. Molecular Mechanisms of Stretch-Induced Electrical Remodeling in the Heart
    ANDREAS AUGUSTINUS WERDICH; Fiscal Year: 2013
    ..abstract_text> ..
  10. K+ Channel Trafficking and Modulation by Mink and MiRP1
    Geoffrey W Abbott; Fiscal Year: 2013
    ....
  11. Microbial Ecology and Theory of Animals Center for Excellence in Systems Biology
    KAREN J GUILLEMIN; Fiscal Year: 2013
    ..Our innovative and integrated approaches to scientific inquiry, education, and outreach will create a fertile training environment for a new and diverse generation of host-microbe System Biologists. ..
  12. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  13. PPG - Mechanisms of Cardiovascular Protection and Disease
    Donald D Heistad; Fiscal Year: 2013
    ..abstract_text> ..
  14. Heart and Muscle K+ Channels: Assembly and Regulation
    Gideon Koren; Fiscal Year: 2013
    ....
  15. Calsequestrin in Ventricular Arrhythmia and Sudden Death
    Bjorn C Knollmann; Fiscal Year: 2013
    ..To test the hypothesis that Casq2 is reduced near RyR2 Ca release channels in cardiac muscle surviving after myocardial infarction ..
  16. 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. ..
  17. A Multi-Scale Approach to Cardiac Arrhythmia: from the Molecule to the Organ
    Gideon Koren; Fiscal Year: 2013
    ....
  18. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  19. Mechanisms of Ventricular Tachycardia in Lipotoxic Cardiomyopathy
    JOHN PEARCE MORROW; Fiscal Year: 2013
    ..This project seeks to understand the pathophysiology of lipotoxic cardiomyopathy that leads to arrhythmias and sudden death by using animal models. ..
  20. Molecular basis of Ca2+ leak in heart
    GEORGE BLAIR WILLIAMS; Fiscal Year: 2013
    ..For the PI, the investigation nicely supports his long-term plan to combine theoretical investigations with practical and informative tests with the prospect of broadening our understanding of cardiac cellular function. ..
  21. Sarcoplasmic reticulum calcium leak and calcium instability in cardiac myocytes
    Eric A Sobie; Fiscal Year: 2013
    ..By developing a quantitative framework for understanding normal and defective calcium release, these studies can help identify thoughtful targets for cardiac therapies ..
  22. Function and Integration of Stem Cell-derived Cardiac Tissue Patch
    Nenad Bursac; Fiscal Year: 2013
    ..The knowledge obtained in this project will allow us to pursue in the future engineering of a functional cardiac tissue patch made of human stem cells for potential clinical applications. ..
  23. THE EFFECTS OF MYOFIBROBLASTS ON ELECTROMECHANICAL FUNCTION OF MODEL HEART TISSUE
    Tetsuro Wakatsuki; Fiscal Year: 2013
    ....
  24. Novel Therapeutic Approaches to Atrial Fibrillation Targeting Intracellular Calci
    ANDREW ROBERT MARKS; Fiscal Year: 2013
    ..A rycal is now in Phase II clinical studies for heart failure and sudden cardiac death and would be available for testing in AF patients. ..
  25. Mechanisms of cardiac Ca dysregulation and arrhythmias in ankyrin B deficiency
    Sanda Despa; Fiscal Year: 2013
    ....
  26. Novel ion channel approaches to reentrant arrythymias
    Ira S Cohen; Fiscal Year: 2013
    ..The selectivity and specificity of these approaches far exceed those of drugs and of ablation and open promising new vistas for arrhythmia treatment and prevention. ..
  27. Model of Timothy Syndrome to Screen Drugs with Induced Pluripotent Stem Cells
    Masayuki Yazawa; Fiscal Year: 2013
    ..The proposed systems to screen a library of compounds to rescue TS phenotypes will provide a platform to find novel lead compounds that would be clinically useful for the treatment of not only TS but also other cardiac arrhythmias. ..