Molecular and genetic mechanisms of cardiac conduction development and disease

Summary

Principal Investigator: Neil C Chi
Abstract: DESCRIPTION (provided by applicant): Every year, approximately 450,000 individuals in the United States die suddenly of cardiac arrhythmias due to disorganized ventricular conduction, with many of these deaths linked to both genetic and environmental factors. However, the identification of these genetic factors and how they work alone, together, or in concert with the environment to modulate the cellular and molecular behavior leading to arrhythmic events is far from complete. Thus, studies which identify novel genetic factors linked to cardiac arrhythmias may aid in diagnosis and treatment of patients predisposed for cardiac arrhythmias. The zebrafish has proven to be an outstanding model for understanding human diseases since it has morphologic and physiologic similarities to mammals, and provides an organism with an array of genomic tools which facilitates large-scale phenotype- based screens. For instance, there are zebrafish mutants whose phenotypes resemble complex human disorders, including common adult cardiac syndromes which result in heart failure and arrhythmias. In several cases, phenotypic similarity between man and fish has been confirmed by molecular definition. More recently, the creation of innovative transgenic tools has resulted in more sophisticated in vivo cellular and physiologic analysis as well as phenotypic-based screens. As a result, using a transgenic-based in vivo optical mapping system to perform a new physiologic-based forward genetic screen, we have assembled a collection of mutations that specifically affect ventricular conduction. Most notably, we have discovered that the dococ (dco) and daredevil (ddl) genes are critical regulators of organized ventricular conduction. dco encodes Gja3/Cx46, a gap junction protein not previously implicated in heart development or function, whereas ddl encodes RhoGa, a zebrafish ortholog of RhoG which may affect Cx46 trafficking. In contrast to cardiac Cx40, 43, and 45, the role of Cx46 in heart development or function remains to be further elucidated. Thus, we hypothesize that Cx46 functions in concert with cardiac Cx40, 43, and 45 to organize ventricular conduction through regulation of intercellular communication between specialized ventricular conduction system cardiomyocytes. Our specific aims are: 1) to elucidate underlying mechanisms of how Cx46 regulates ventricular conduction;2) to determine whether Cx46 cardiac function is conserved in the mammalian cardiac conduction system, and 3) to investigate underlying mechanisms by which rhoga regulates ventricular conduction. Overall, the combination of cellular, molecular and physiologic studies proposed in this project will provide new and in-depth insight into mechanisms of human ventricular arrhythmias. These studies may prove rewarding for prognosis and diagnosis of patients susceptible to sudden cardiac death as well as for developing therapeutic options aimed at maintaining and/or improving overall cardiac conduction.
Funding Period: 2011-07-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Flexible microelectrode arrays to interface epicardial electrical signals with intracardial calcium transients in zebrafish hearts
    Fei Yu
    Biomedical Engineering and Cardiovascular Medicine, University of Southern California, Los Angeles, CA, USA
    Biomed Microdevices 14:357-66. 2012
  2. pmc BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes
    Ting Ting Hong
    Cardiovascular Research Institute, University of California, San Francisco, CA, USA
    Heart Rhythm 9:812-20. 2012
  3. ncbi Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease
    Bilge Yoruk
    Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8
    Dev Biol 362:121-31. 2012
  4. pmc Zebrafish models in cardiac development and congenital heart birth defects
    Shu Tu
    Department of Medicine, Division of Cardiology, University of California, San Diego, CA 92093 0613J, USA
    Differentiation 84:4-16. 2012
  5. pmc UBIAD1-mediated vitamin K2 synthesis is required for vascular endothelial cell survival and development
    Jeffrey M Hegarty
    Department of Medicine, University of California, La Jolla, CA 92093 0613J, USA
    Development 140:1713-9. 2013
  6. pmc In vivo cardiac reprogramming contributes to zebrafish heart regeneration
    Ruilin Zhang
    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA
    Nature 498:497-501. 2013
  7. pmc 3-OST-7 regulates BMP-dependent cardiac contraction
    Shiela C Samson
    Department of Neurobiology and Anatomy, University of Utah Molecular Medicine Program, Salt Lake City, Utah, United States of America
    PLoS Biol 11:e1001727. 2013
  8. pmc The atypical Rho GTPase, RhoU, regulates cell-adhesion molecules during cardiac morphogenesis
    Michael Dickover
    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA 92093 0613J, USA
    Dev Biol 389:182-91. 2014

Detail Information

Publications8

  1. pmc Flexible microelectrode arrays to interface epicardial electrical signals with intracardial calcium transients in zebrafish hearts
    Fei Yu
    Biomedical Engineering and Cardiovascular Medicine, University of Southern California, Los Angeles, CA, USA
    Biomed Microdevices 14:357-66. 2012
    ..These microelectrodes therefore provide a real-time analytical tool for monitoring conduction phenotypes of small vertebral animals with a high temporal and spatial resolution...
  2. pmc BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes
    Ting Ting Hong
    Cardiovascular Research Institute, University of California, San Francisco, CA, USA
    Heart Rhythm 9:812-20. 2012
    ..2 channels at cardiac T tubules. Bridging integrator 1 (BIN1) is a membrane scaffolding protein that causes Cav1.2 to traffic to T tubules in healthy hearts. The mechanisms of Cav1.2 trafficking in heart failure are not known...
  3. ncbi Ccm3 functions in a manner distinct from Ccm1 and Ccm2 in a zebrafish model of CCM vascular disease
    Bilge Yoruk
    Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 1A8
    Dev Biol 362:121-31. 2012
    ..CCM3/GCKIII activity provides a novel therapeutic target for CCMs, as well as for the modulation of vascular permeability...
  4. pmc Zebrafish models in cardiac development and congenital heart birth defects
    Shu Tu
    Department of Medicine, Division of Cardiology, University of California, San Diego, CA 92093 0613J, USA
    Differentiation 84:4-16. 2012
    ....
  5. pmc UBIAD1-mediated vitamin K2 synthesis is required for vascular endothelial cell survival and development
    Jeffrey M Hegarty
    Department of Medicine, University of California, La Jolla, CA 92093 0613J, USA
    Development 140:1713-9. 2013
    ....
  6. pmc In vivo cardiac reprogramming contributes to zebrafish heart regeneration
    Ruilin Zhang
    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA
    Nature 498:497-501. 2013
    ....
  7. pmc 3-OST-7 regulates BMP-dependent cardiac contraction
    Shiela C Samson
    Department of Neurobiology and Anatomy, University of Utah Molecular Medicine Program, Salt Lake City, Utah, United States of America
    PLoS Biol 11:e1001727. 2013
    ..Together these results reveal 3-OST-7 as a key component of a novel pathway that constrains BMP signaling from ventricular myocytes, coordinates sarcomere assembly, and promotes cardiac contractile function. ..
  8. pmc The atypical Rho GTPase, RhoU, regulates cell-adhesion molecules during cardiac morphogenesis
    Michael Dickover
    Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, CA 92093 0613J, USA
    Dev Biol 389:182-91. 2014
    ..Failure to properly form these cell adhesions during cardiac development may lead to structural heart defects and mechanistically account for the cellular events that occur in certain human congenital heart diseases. ..

Research Grants30

  1. Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship
    Steven Poelzing; Fiscal Year: 2013
    ..This model will include all the data collected from Drs. Poelzing, and Salama. The mathematical model will be validated against all interventions proposed in the animal experiments. ..
  2. Cardiac Ion Channel Regulation
    Isabelle Deschenes; Fiscal Year: 2013
    ....
  3. 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. ..
  4. Heart and Muscle K+ Channels: Assembly and Regulation
    Gideon Koren; Fiscal Year: 2013
    ....
  5. MicroRNAs, cardiac development and function
    Da Zhi Wang; Fiscal Year: 2013
    ..Aim #2. To investigate the molecular events mediated by Csm, a cardiac-specific RNA helicase, in miRNA pathway. Aim #3. To define the role of Csm in cardiac development and cardiomyocyte proliferation. ..
  6. A Multi-Scale Approach to Cardiac Arrhythmia: from the Molecule to the Organ
    Gideon Koren; Fiscal Year: 2013
    ....
  7. Biomarkers of Heart Regeneration
    Ravi Karra; Fiscal Year: 2013
    ..Kenneth Poss, PhD, a pioneer and leader in regenerative biology. We will collaborate with the Duke Clinical Research Institute, allowing for the ideal training experience for a translational research career. ..
  8. Elucidating the molecular mechanisms regulating embryonic cardiac rhythmicity
    Jau Nian Chen; Fiscal Year: 2013
    ..The studies in this proposal will help elucidate cellular and molecular mechanisms underlying cardiac fibrillation and ultimately contribute to the development of new preventive and therapeutic approaches. ..
  9. Microsensors to Study Electrical and Mechanical Coupling of Injured Myocardium
    Tzung K Hsiai; Fiscal Year: 2013
    ....
  10. Multi-scale Systems Model of Murine Heart Failure
    Andrew D McCulloch; Fiscal Year: 2013
    ....
  11. ION CHANNEL REGULATION AND MODULATION IN CARDIAC MUSCLE
    Jeanne M Nerbonne; Fiscal Year: 2013
    ....
  12. 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. ..
  13. The molecular mechanisms underlying arrhythmogenic right ventricular dysplasia/ca
    Farah Sheikh; Fiscal Year: 2013
    ..These studies will identify molecular pathways that are essential for the progression of ARVD/C and thereby improve our general understanding of this disease, as well as identify therapeutic targets for treating this fatal disease. ..
  14. Mechanisms of cardiac Ca dysregulation and arrhythmias in ankyrin B deficiency
    Sanda Despa; Fiscal Year: 2013
    ....
  15. UNDERSTANDING THE ROLES OF MIR-1S IN REGULATING HEART DEVELOPMENT
    Yong Zhao; Fiscal Year: 2013
    ..The proposed studies may uncover new fundamental mechanisms of heart disease. Insights from the studies will facilitate steps towards understanding of functions of numerous miRNAs in human diseases. ..