MIR-1-2 FUNCTION IN CARDIAC CONDUCTION SYSTEM DEVELOPMENT AND MAINTENANCE

Summary

Principal Investigator: Yong Zhao
Abstract: DESCRIPTION (provided by applicant): Disorders of the cardiac conduction system can cause arrhythmias which is the major causes of sudden cardiac death in the patients with cardiovascular diseases. A deep understanding of CCS development and maintenance will likely offer new therapeutic strategies for prevention and therapy of arrhythmias. The PI previously described two muscle-specific miRNAs, miR-1-1 and miR-1-2, that are encoded by distinct genomic loci but share an identical mature sequence. The PI recently found that both miR- 1s are enriched in the CCS progenitors during cardiogenesis, and that both continue to be highly expressed in the whole CCS throughout development and in adulthood. miR-1s repress cell proliferation. Overexpression of miR-1-2 causes bradycardia and arrhythmias. Surviving miR-1-2 null mice exhibit bradycardia and develop cardiac conduction defects after birth but are without obvious cardiac structural abnormalities. The cardiac conduction defects in the miR-1-2 null adults are analogous to bundle branch block in patients, which are caused by abnormalities in the VCS. The PI hypothesizes that miR-1-2 plays a key role in restricting the cell cycle progression of CCS cells, and that it is a critical regulator controlling proper differentiation and maintenance of various CCS lineages. To test these hypotheses, the PI proposes to determine the role of miR-1-2 in regulating specification and proliferation of the CCS (Specific Aim 1);to determine how miR-1-2 establishes a precise level of calcium signaling, ion channels, and connexins during differentiation and maintenance of the CCS (Specific Aim 2);to identify affected genetic pathways upon loss of miR- 1-2 that are critical for development and maintenance of the CCS (Specific Aim 3). Completion of the proposed studies will elucidate new fundamental mechanism underlying development and function of the CCS, which will provide insights into cardiac arrhythmias and inform the development of novel strategies for treating them.
Funding Period: 2011-05-02 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Inducible gene deletion in the entire cardiac conduction system using Hcn4-CreERT2 BAC transgenic mice
    Meng Wu
    Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
    Genesis 52:134-40. 2014
  2. pmc Multifaceted roles of miR-1s in repressing the fetal gene program in the heart
    Yusheng Wei
    1 Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1040, New York, NY 10029, USA 2 Current address College of Life Sciences, Peking University, Beijing 100871, China
    Cell Res 24:278-92. 2014

Detail Information

Publications2

  1. pmc Inducible gene deletion in the entire cardiac conduction system using Hcn4-CreERT2 BAC transgenic mice
    Meng Wu
    Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
    Genesis 52:134-40. 2014
    ..Our Hcn4-CreERT2 BAC transgenic line will be an invaluable genetic tool with which to dissect the developmental control of CCS and arrhythmias...
  2. pmc Multifaceted roles of miR-1s in repressing the fetal gene program in the heart
    Yusheng Wei
    1 Mindich Child Health and Development Institute, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1040, New York, NY 10029, USA 2 Current address College of Life Sciences, Peking University, Beijing 100871, China
    Cell Res 24:278-92. 2014
    ..We conclude that miR-1 and its primary target ErrĪ² act together to regulate the transition from prenatal to neonatal stages by repressing the cardiac fetal gene program. Loss of this regulation leads to a neonatal DCM. ..

Research Grants30

  1. FAK signaling in cardiac growth and hypertrophy
    Joan M Taylor; Fiscal Year: 2013
    ..Furthermore, these cells lose the ability to divide shortly after birth, thus any damage to the heart can cause irreversible loss of function. ..
  2. Purkinje Cells and Arrhythmia Mechanisms
    Glenn I Fishman; Fiscal Year: 2013
    ..Our research is directed toward understanding the mechanisms responsible for these lethal arrhythmias and identifying potential new therapeutic targets. ..
  3. Role of serum- and glucocorticoid-regulated kinase-1 in electrical remodeling
    Anthony Rosenzweig; Fiscal Year: 2013
    ..Thus understanding SGK1's role in the heart could have important practical implications, and the current application would help advance our understanding of the potential of SGK1 as a therapeutic target. ..
  4. Identification of a Stretch-Activated Channel with a Role in Cardiac Development
    Dipayan Chaudhuri; Fiscal Year: 2013
    ..By identifying key molecules that sense blood pressure, we hope to gain new insight into how these diseases develop and establish these sensors as targets for the design of novel drugs. ..
  5. 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. ..
  6. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  7. 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. ..
  8. A Multi-Scale Approach to Cardiac Arrhythmia: from the Molecule to the Organ
    Gideon Koren; Fiscal Year: 2013
    ....
  9. Cardiac Stem Cells and Angiomyogenesis
    Jan Kajstura; Fiscal Year: 2013
    ....
  10. Connexin Distribution in Physiological Versus Pathological Cardiac Hypertrophy
    Michael R Zile; Fiscal Year: 2013
    ..pathological hypertrophy, with ex- tensively characterized cytoskeletal properties in each setting. ..
  11. Dedifferentiation of cardiomyocytes into cardiac progenitor cells
    Eduardo Marban; Fiscal Year: 2013
    ..We will test the idea that mature heart cells can go backwards and regain the features of innate progenitor cells, an idea which has important biological, pathophysiological and therapeutic implications. ..
  12. Myofibril disassembly during neonatal heart muscle cell proliferation
    Bernhard Kuhn; Fiscal Year: 2013
    ..The results of this research should increase the translational potential of regenerative strategies that stimulate cardiomyocyte proliferation. ..