Genomes and Genes
MIR-1-2 FUNCTION IN CARDIAC CONDUCTION SYSTEM DEVELOPMENT AND MAINTENANCE
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
- Inducible gene deletion in the entire cardiac conduction system using Hcn4-CreERT2 BAC transgenic miceMeng 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...
- Multifaceted roles of miR-1s in repressing the fetal gene program in the heartYusheng 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 Errβ 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. ..
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- Blood Pressure Regulation: Novel Roles for the KidneyPablo 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. ..
- Center for Neuroplasticity at the University of Puerto RicoSteven 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. ..
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- Cardiac Stem Cells and AngiomyogenesisJan Kajstura; Fiscal Year: 2013....
- Connexin Distribution in Physiological Versus Pathological Cardiac HypertrophyMichael R Zile; Fiscal Year: 2013..pathological hypertrophy, with ex- tensively characterized cytoskeletal properties in each setting. ..
- Dedifferentiation of cardiomyocytes into cardiac progenitor cellsEduardo 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. ..
- Myofibril disassembly during neonatal heart muscle cell proliferationBernhard Kuhn; Fiscal Year: 2013..The results of this research should increase the translational potential of regenerative strategies that stimulate cardiomyocyte proliferation. ..