Michael Harris Nathanson MD, PhD

Gladys Phillips Crofoot Professor of Medicine (Digestive Diseases) and Professor of Cell Biology; Section Chief, Digestive Diseases; Director, Yale Liver Center; Director, Center for Cell and Molecular Imaging

Research Interests

Mechanisms and effects of calcium signals in polarized epithelia; Effect of spatial organization of calcium signals on organ function regulation; Factors that organize Ca2+ waves in hepatocytes; Organization and effects of Ca2+ waves in cholangiocytes; Mechanisms and effects of Ca2+ signals in the nucleus

Current Projects

  • NIH P01 DK57751 (PI: M.H. Nathanson). Regulation of liver by nuclear calcium signaling. Duration: 4/1/06-3/31/11. The major goals of this project are to determine the mechanisms by which calcium is regulated in the nucleus of hepatocytes, and to determine the functional effects of nuclear calcium signals in liver.
  • NIH R01 DK45710 (PI: M.H. Nathanson). Calcium waves in hepatocytes: mechanisms and effects. Duration: 4/1/10-3/31/15. The major goals of this project are to determine the subcellular location and function of the different InsP3 receptor isoforms in hepatocytes and to determine if the different isoforms exert distinct effects on organization of calcium waves and regulation of secretion by calcium.
  • NIH R01 DK61747 (PI: B.E. Ehrlich, M.H. Nathanson [multiple PI’s] ). Regulation of cholangiocytes by InsP3 receptor isoforms. Duration: 5/1/09-4/30/13. Dr. Nathanson is co-investigator on this award. The major goals of this project are to determine how InsP3 receptors regulate calcium signaling and bicarbonate secretion in intrahepatic bile ducts.

Research Summary

My laboratory studies the mechanisms and effects of calcium signals in polarized epithelia. One aspect of our work is to define how calcium signals are
differentially regulated in the nucleus and cytoplasm. This involves identification of distinct calcium stores and release mechanisms in the nucleus, and we are
examining whether and how these are activated selectively by growth factors. The second aspect of our work is to examine how calcium waves and other calcium signals regulate secretion in polarized epithelia. Calcium waves preferentially begin in, the apical region of most secretory epithelia, and we are in the process of defining the mechanisms responsible for this. We also are using an adenoviral antisense approach to understand the relative roles of each IP3 receptor isoform in regulating calcium signaling and secretion in vitro and in vivo. Another major focus is to examine intercellular communication of second messenger signals and to establish the mechanism by which gap junctions act in coordinating intercellular spread of Ca2+ waves in isolated pairs and triplets of cells.

Selected Publications

  • Mennone, A., and Nathanson, M.H.: Needle-based confocal laser endomicroscopy to assess liver histology in vivo. Gastrointestinal Endoscopy, in press.
  • Cruz, L.N., Guerra, M.T., Kruglov, E.A., Mennone, A., Garcia, C.R.S., Chen, J., and Nathanson, M.H.: Regulation of multidrug resistance-associated protein 2 by calcium signaling in mouse liver. Hepatology 52:327-337, 2010.
  • Rodrigues, M.A., Gomes, D.A., Leite, M.F., and Nathanson, M.H.: Insulin induces calcium signals in the nucleus of rat hepatocytes. Hepatology 48: 1621-1631, 2008.
  • Gomes, D.A., Rodrigues, M.A., Leite, M.F., Gomez, M.V., Varnai, P., Balla, T., Bennett, A.M., and Nathanson, M.H.: c-Met must translocate to the nucleus to initiate Ca2+ signals. J. Biol. Chem. 283: 4344-4351, 2008.
  • Rodrigues, M.A., Gomes, D.A., Grant, W., Leite, M.F., Bennett, A.M., Zhang, L., Lam, W., Cheng, Y-C., and Nathanson, M.H.: Nucleoplasmic calcium regulates cell growth. J. Biol. Chem. 282: 17061-17068, 2007.
  • Echevarria, W., Leite, M.F., Guerra, M.T., Zipfel, W.R., and Nathanson, M.H.: Regulation of calcium signals in the nucleus by a nucleoplasmic reticulum. Nature Cell Biology 5: 440-446, 2003.
  • Leite, M.F., Thrower, E.C., Echevarria, W., Koulen, P., Hirata, Bennett, A.M., Ehrlich, B.E., and Nathanson, M.H.: Nuclear and cytosolic calcium are regulated independently. Proc. Natl. Acad. Sci. USA 100: 2975-2980, 2003.
  • Hagar, R.E., Burgstahler, A.D., Nathanson, M.H., and Ehrlich, B.E.: Type III InsP3 receptors stay open in the presence of elevated calcium. Nature 396: 81-84, 1998.

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