|
Mrinalini C. Rao, PhDProfessorPhysiology and BiophysicsMolecular Regulation of Epithelial Ion Transport |
Research Interest:
Research in Dr. Rao's laboratory focuses on elucidating the molecular mechanisms underlying hormonal and neurotransmitter mediated regulation of physiological processes, in particular, those modulating ion transport across epithelial cells. The major emphasis is on the gastrointestinal tract, where such studies help elucidate the basis of diseases ranging from infectious diarrheas to inflammatory bowel disease and cystic fibrosis (CF). In general, epithelial ion transport processes are complex and are involved in the vectorial movement of salt and water as well as in routine cellular functions such as the regulation of growth, volume and pH.
This laboratory has been successful in establishing primary cultures of human and rabbit colonic epithelia, considered a difficult task, since intestinal epithelial cells do not lend themselves readily to isolation and culture. This has facilitated the study of various ion transporters including chloride channels, such as the cystic fibrosis transmembrane conductance regulator (CFTR), the sodium-potassium-chloride cotransporter (NKCC) and the sodium/hydrogen exchangers (NHE). Examination of the regulation of these transporters by cAMP, cGMP and calcium signal transduction cascades is a primary focus of this laboratory. For example, this laboratory has demonstrated the presence of second messenger-specific protein kinases and CFTR in the human colon and that the colon of CF subjects exhibits impaired Cl- transport in response to cAMP-, cGMP- and calcium stimulation. This laboratory has also demonstrated the expression of genes involved in ion transport in mammary epithelial cells. In addition, mammotropic hormones, such as prolactin, have been shown to modulate sodium and chloride transport in these cells.
Recent efforts in the laboratory are concentrated on the exciting new areas of compartmentalization, including the study of scaffolding proteins and of cross-talk between various signaling pathways. For example, changes in cGMP and calcium signaling have been observed during development in the colon. The precise site/step of this differential regulation has been identified to the lack of appropriate expression of specific gene products in the signaling cascade. Two exciting candidates are the localization of phospholipase C and the expression of protein kinase C delta. An elucidation of the individual molecular events will help in the understanding of the molecular basis of varied physiological processes such as milk production and intestinal secretions.
Selected Publications:
1) Chang, E.B. and Rao, M.C. Intestinal Water and Electrolyte Transport: Mechanisms of Physiological and Adaptive Responses. In: Physiology of the Gastrointestinal Tract, Third Edition. Edited by Leonard R. Johnson. Raven Press, New York, p. 2027-2081, 1994.
2) Rao, M.C., Bissonnette, G.B., Mahaffey, T. and Goldstein, J.L. Rectal epithelial expression of protein kinase A-phosphorylation of cystic fibrosis transmembrane conductance regulator. Gastroenterology 106:890-898, 1994.
3) Desai, G.N., Sahi, J., Reddy, P.M., Vidyasagar, D. and Rao, M.C. Chloride transport in primary cultures of mammalian colonocytes at different stages of development. Gastroenterology 111:1541-1550, 1996.
4) Bhartur, S.B., Bookstein, C., Musch, M.W., Ballarin, L., Chang, E.B. and Rao, M.C. Detection and regulation of a chicken-specific intestinal Na+/H+ exchanger. Comparative Biochemistry and Physiology 118A, #3:883-889, 1997.
5) Sahi, J., Nataraja, S.G., Layden, T.J., Moyer, M.P. and Rao, M.C. Cl- transport in an immortalized human epithelial cell line (NCM460) derived from the normal transverse colon. American Journal Physiology 275 (Cell Physiology 44):C1048-C1057, 1998.
6) Bhartur, S.B., Musch, M.W., Chang, E.B. and Rao, M.C. A unique Na+/H+ exchanger, analogous to NHE1, in the chicken embryonic fibroblast. American Journal of Physiology 276 (Regulatory, Integrative and Comparative Physiology 45):R838-R846, 1999.
7) Selvaraj, N.G., Prasad, R., Goldstein, J.L. and Rao, M.C. Evidence for the presence of cGMP dependent protein kinase-II in human distal colon and in T84, the colonic cell line. Biochimica et Biophysica Acta 1498, 32-43, 2000.
8) Venkatasubramanian, J., Sahi, J., and Rao, M.C. Ion transport during growth and differentiation. Annals of New York Academy Of Sciences 915: 357-372, 2000.
9) Nataraja, S.G., Omi, E., Gibori, G. and Rao, M.C. JAK2 regulates prolactin-mediated chloride transport in mouse mammary epithelial cell through tyrosine phosphorylation of Na+-K+-2Cl- cotransporter. Molecular Endocrinology 14:2054-2065, 2000.
10) Venkatasubramanian, J., Selvaraj, N.G., Carlos, M., Skaluba, S., Rasenick, M.M. and Rao, M.C. Differences in Ca2+ signaling underlies age-specific differences in regulation of colonic chloride transport by bile acids and Secretagogues. American Journal of Physiology 280; (Cell Physiology 49) C646-C658, 2001.
11) Musch, M. W., Bookstein, C.., Rocha,F., Lucioni, A., Ren,H., Daniel, J., Xie, Y., McSwine,R.L., Mrinalini C. Rao, M.C., John Alverdy, J.. and Eugene B. Chang, E.B. Region-specific adaptation of apical Na/H exchangers after extensive proximal small bowel resection. Am J Physiol (Gastrointest Liver Physiol) 283: G975–G985, 2002.
12) Rao, M.C. Oral rehydration therapy: New explanations for an old remedy. Annual Review of Physiology, 2004 Vol 66 :385-417. AR Reviews in Advance10.1146/annurev.physiol.66.032902. 134726
13) Prasad, R., Venkatasubramanian, J., Amde, M., and Rao, M.C. Phospholipase C and src tyrosine kinases mediate neurotensin-stimulated Cl- secretion in rabbit proximal colon. Digestive Disease Sciences, 49: 1318-1326, 2004.
14) Weihrauch, D., Kanchanapoo, J., Ao, M., Piyachutarawat, P. and Rao, M.C. Weanling but not adult rabbit colon absorbs bile acids: Flux linked to expression of putative bile acid transporters. Am J Physiol (Gastrointest Liver Physiol, 2006 Mar;290(3):G439-50. Epub 2005 Sep 15.
15) Kanchanapoo, J., Rao, M.C., Suksamrarn, A., and Piyachaturawat, P . Inhibitory effects of choleretic hydroxyacetophenones on ileal bile acid transport in rats. Life Sci . 2006 Feb 28;78(14):1630-6.
16) Carlos M.A., Nwagwu C.,Ao M., Venkatasubramanian J., Boonkaewwan C., Prasad R., Khan Chowdhury S.A., Vidyasagar D., Rao M.C . Epidermal Growth Factor (EGF) Stimulates Chloride Transport in Primary Cultures of Weanling and Adult Rabbit Colonocytes. J Pediatr Gastroenterol Nutr . 2007 Mar;44(3):300-11.
09/10/07