Ravi P. Misra, Ph.D.

Professor

Dr. Misra obtained his Bachelor of Arts degree in Microbiology from Rutgers College in New Jersey in 1979 and his Doctorate degree in Biochemistry from New York University School of Medicine in 1988. He was a Postdoctoral Research Fellow at Harvard Medical School where he studied the molecular control of growth factor induced transcriptional regulation of the c-fos proto-oncogene. Dr. Misra joined the faculty of the Biochemistry Department at the Medical College of Wisconsin in 1993.

Contact Information

rmisra@mcw.edu
Phone: (414) 456-8433
Fax: (414) 456-6510

Research Interests

In vivo mechanisms controlling developmental and cardiac-specific gene expression

My major research interest is to understand the biochemical mechanisms by which control expression of genes at the transcriptional level. Our current work concerns (1) understanding the mechanism by which the Serum Response Factor (SRF) mediates gene expression during early cardiogenesis, and (2) understanding mechanisms controlling the in vivo expression of the SRF gene itself during early development.

One of the overall objectives of our research is to elucidate underlying molecular mechanisms involved in cardiac function and heart formation. Congenital cardiovascular anomalies are the most common form of human birth defect with a recorded instance of 1 per 200 live births per year in North America. There is therefore considerable interest in understanding the molecular and genetic bases of these diseases. Underlying congenital heart defects is the complexity of cardiovascular development. Proper heart development requires the precise expression at the temporal and spatial level of a complex cast of structural and regulatory proteins. Alterations in either the function of these proteins, their time or location of expression, or their abundance relative to other critical proteins can have drastic consequences for cardiac development ranging from embryonic lethality to functional malformations of the heart that can lead to significant cardiomyopathies. One way in which proteins can be become misexpressed is by aberrant regulation of expression of the genes that encode them. It is therefore important to understand the mechanisms that regulate normal expression of these proteins during formation of the heart. However, due to the significant limitations of the current technologies used to study embryonic gene regulation and protein function this has been difficult to address. In our studies we are using a novel sophisticated mouse transgenic approach to study the molecular mechanisms involved in controlling regulation of a transcriptional regulatory protein, the serum response factor (SRF).

Recent evidence in rodent systems indicates that the serum response factor (SRF), a member of the MADS (MCM1, Agamous and Deficiens, SRF) box family of transcription factors, is a critical regulator of cardiac development and function. SRF has been shown to regulate various cardiac and skeletal muscle specific genes necessary for normal heart development and function, including the cardiac and skeletal actin, dystrophin, myosin light chain, and atrial natriuretic peptide genes. Consistent with this, cardiac specific overexpression of SRF in transgenic animals results in reinduction of an embryonic program of gene expression that can lead to dramatic cardiac hypertrophic and myopathic phenotypes that mimic those observed during the initial development of congestive heart failure in humans. However, knock-out of the SRF gene is embryonic lethal prior to cardiac differentiation. Therefore, despite a central place for SRF in heart function and development the role of SRF in heart formation in vivo has not been carefully investigated.

The results of our ongoing studies are likely to give new insight into SRF-mediated gene regulation as well as cardiomyogenesis and heart function. The techniques and strategies developed in these studies will not only yield important information regarding the tissue specific, spatial, and developmental controls on SRF gene expression, but they should also establish the experimental basis for powerful new technologies that can be used to analyze in vivo gene function and regulation.

Selected Publications

"Role of the serum response factor in regulating contractile apparatus gene expression and sarcomeric integrity in cardiomyocytes." R.O. Balza and R.P. Misra, J Biol. Chem., 281:6498-6510, (2006)

"SRF-dependent gene expression in isolated cardiomyocytes: Regulation of genes involved in cardiac hypertrophy." T.J. Nelson, R.O. Balza, Q. Xiao, and R.P. Misra, J Mol. Cell. Cardiology, 39:479-489, (2005)

"Restricted inactivation of serum response factor to the cardiovascular system." J.M. Miano, N. Ramanan, M.A. Georger, K.L. De Mesy Bentley, R.L. Emerson, R.O. Balza, Q. Xiao, H. Weiler, D.D. Gintly, and R.P. Misra, Proc. Natnl. Acad,Sci. USA, 101:17132-17137, (2004)

"Conserved enhancer in the serum response factor promoter controls expression during early coronary vasculogenesis.", T.J. Nelson, S.A. Duncan and R.P. Misra, Circ Res. 94:1059-66, (2004)

"Gene targeting in the mouse: advances in introduction of transgenes into the genome by homologous recombination.", R.P. Misra and S.A. Duncan, Endocrine. 19:229-38, (2002)

"Generation of single-copy transgenic mouse embryos directly from ES cells by tetraploid embryo complementation", R.P. Misra, S.K. Bronson, Q. Xiao, W. Garrison, J. Li, R. Zhao, and S.A.Duncan, BioMedCentral Biotechnology 1:12, (2001)

"Early postnatal cardiac changes and premature death in transgenic mice overexpressing a mutant form of serum response factor." X.M. Zhang, Chai, G.J. Azhar, P. Sheridan, J.H. Brown, K. Khrapko, A.M. Borras, J. Lawitts, Misra, R.P., and J.Y. Wei J. Biol. Chem. 276:40033-40040, (2001)

"Cardiomyopathy in transgenic mice with cardiac-specific overexpression of the serum response factor", X.M. Zhang, G. Azhar, J. Chai, P. Sheridan, K. Nagano, T. Brown, J.H. Yang, K. Khrapko, A.M. Borras, J. Lawitts, R.P. Misra, and J.Y. Wei Amer. J. Physiol. 280:H1782-H1792, (2001)

"Serum response factor dependent regulation of the smooth muscle calponin gene", J.M. Miano, M.J. Carlson, J.A. Spencer, and R.P. Misra. J. Biol. Chem., Mar 31;275(13):9814-22 (2000)