Steve Fisher, MD
Phone: 216-368-0488
Fax: 216-368-0556
E-mail: steve.fisher@case.edu
Research Summary:
My laboratory use basic cell and molecular biological research techniques to address fundamental questions regarding the regulation of gene expression and the development and function of the cardiovascular system. In one model system we address the control mechanisms for the generation of vascular smooth muscle phenotypic diversity. We have proposed that the regulated splicing of a myosin phosphatase (MP) alternative exon serves to fine tune VSM responses to NO/cGMP signaling. The splicing of this exon is highly regulated during developmental specification, and responsive to changes in blood flow. Very recent data suggests that the Transformer proteins, proteins that were originally identified by their ability to specify female phenotype in flies, is a master regulator of MP splicing in development and disease. We are planning to test this model using transgenic and knock-out strategies.
The second model regards the role of hypoxia and the hypoxia-inducible transcription factor (HIF) in heart development. We have proposed a model in which hypoxia signaling through HIF triggers the remodeling of the embryonic cardiac outflow tract in the transition to a dual series circulation. The processes that hypoxia is thought to regulate in this context include programmed cell death and recruitment of endothelial progenitor cells for coronary vasculogenesis. This project uses chick and mouse models in gain-and-loss of function experiments to address this question.
Recent publications:
1.Payne MC, Hai-Ying Zhang, Joseph Benoit and S Fisher Dynamic changes in myosin phosphatase expression in a model of portal hypertension Am J Physiol Heart 2004, 286, H1801-1810
2. Huang QQ, Fisher S, Brozovich F Unzipping the role of myosin light chain phosphatase in smooth muscle cell relaxation J Biol Chem,2004, 279:597-602
3. Shukla S, Dirksen W, LeGuinier, C Breathnach R and Fisher S TIA-1 is a necessary but not sufficient for tissue-specific splicing myosin phosphatase targeting subunit 1, J Biol Chem, 2004, 279, 13668-13676
4. Schaeffer K, Doughman YQ, Fisher S, Watanabe M Dynamic Patterns of Apoptosis in the Developing Heart, Dev Dyn, 2004, 229:489-499
5. Sugishita Y, Watanabe M, Fisher S Role of myocardial hypoxia in the remodeling of the embryonic avian cardiac outflow tract, Dev Biol, 2004, 267, 294-308
6. Sallee D, Watanabe M and Fisher S Fas ligand gene transfer to the embryonic heart induces the program of cell death and outflow tract defects, Dev Biol, 2004, 267, 309-319
7. Sugishita Y, Leifer D, Agani F, Watanabe M, Fisher S Hypoxia-responsive signaling regulates the apoptosis-dependent remodeling of the embryonic avian cardiac outflow tract, Dev Biol, 2004, 273:285-296
8. Sugishita Y, Watanabe M, Fisher S The development of the myocardial portion of the embryonic outflow tract provides novel insights into cardiac differentiation and remodeling, Trends in Cardiovascular Medicine, 2004, 14:235-241
9.Shukla S, Dirksen W, LeGuinier, C Breathnach R and Fisher S Competition between TIA-1 and PTB for binding to a U-rich cis-element determine the tissue-specific splicing of myosin phosphatase targeting subunit 1, RNA, 2005, 11:1725-36
10. Payne MC, Hai-Ying Zhang, Dominic Prodoscimo and S Fisher Myosin phosphatase isoform switching in vascular smooth muscle development, J Mol Cell Cardiol, 2006,40:274-282
11. Wikenhisre J, Doughman Q, Fisher SA and Watanabe M Differential levels of tissue hypoxia in in the developing chick heart, Dev Dyn, 2006, 235:115-123
12. Zhang HY and Fisher SA Conditioning effect of blood flow on resistance artery smooth muscle myosin phosphatase, Circ Res, 2007,100:730-737
13. Fisher S and Burggren W Role of hypoxia in the development and evolution of the cardiovascular system, Anti-oxidants and Redox Signaling, 2007,9:152-159
14. Fisher SA The developing embryonic cardiac outflow tract is highly sensitive to oxidant stress. Dev Dyn. 2007 Dec;236(12):3496-502
15. Lu Y, Zhang HY, Osol G and Fisher S Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy AJP-Cell, in press
16. Liu HL and Fisher SA Hypoxia-inducible transcription factor-1a triggers an autocrine survival pathway during embryonic cardiac outflow tract remodeling, Circ Res, in press
17. Zhang HY, Lee HJ and Fisher SA Induction of PDE5 and de-sensitization to endogenous NO signaling in a systemic circulation, submitted
18. Shukla S and Fisher SA Identification of a novel pathway for smooth muscle phenotypic specification involving TRa2b, Circ Res, in press
