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------------------------------------------------------------------------------------------------- Curriculum Vitae M.D.,
Univ. of Buenos Aires, Fac. de Medicina 1976 ------------------------------------------------------------------------------------------------- Research Interests Many eukaryotic cells are polarized (asymmetric). Among them, epithelial cells form barriers that separate the external environment from the internal milieu. The polarization of their plasma membrane into apical (luminal) or basolateral domains enable the tissue to absorb or secrete. Mutations of polarized epithelial proteins result in common genetic diseases such as cystic fibrosis or polycystic kidney disease. My laboratory is interested in the molecular mechanisms involved in the acquisition and maintenance of polarity, which can be categorized in three general groups: membrane traffic, organization of the cytoskeleton and polarized signaling. In addition, submembrane scaffolds ultimately attached to the cytoskeleton recruit cytosolic proteins that become polarized and serve, in turn, to support signaling localized to the apical or basolateral domains. We are currently engaged in two different projects: (1) We are interested in the molecular mechanisms that control the localization of the minus ends of microtubules to the apical domain, which fail until the late stages of the recovery after ischemia (lack of blood supply) in the kidney. Our goal is to identify the proteins involved in the minus-end tethering, and their regulation by signaling cascades. Ultimately, we seek to identify the abnormal signaling in the late stages of ischemic acute renal failure responsible for the disorganization of microtubules. (2) The assembly of the apical ezrin scaffold is responsible for the function and regulation of ion channels (e.g. CFTR and NHE-3) by PKA. In turn, this molecular machinery is the effector of cholera and other toxins in the intestine that are responsible for thousands of deaths worldwide. The focus of this project is to identify the mechanisms of ezrin recruitment to the apical domain and its activation to finally assemble in the appropriate scaffold as well as the recruitment of the necessary kinases. The long term goal is to understand how apical scaffolds are assembled, what signals are required, and to be able to manipulate this assembly as part of therapeutic interventions. From a technical standpoint, this project is also geared to prepare the biological reagents necessary for stable gene transplantation in the intestine. Funded by the National Institute of Diabetes, Digestive and Kidney diseases. ------------------------------------------------------------------------------------------------- Selected Publications (For a more comprehensive list go to the Salas Lab Page) Wald F.A., Oriolo A.S., Mashukova A, Fregien, N.L., Langshaw, A.H., and Salas P.J. 2008. Atypical Protein Kinase C (iota) activates ezrin in the apical domain of intestinal epithelial cells. J. Cell Science 121(Pt 5):644-54. Oriolo A.S., Wald F.A., Ramsauer V.P., and Salas P.J.I. 2007. Intermediate filaments: a role in epithelial polarity. Exp. Cell Res. 313(10):2255-2264. Cover art. Oriolo, A.S., Wald, F.A., Canessa, G., and Salas, P.J. 2007. GCP6 binds to intermediate filaments: a novel function of keratins in the organization of microtubules in epithelial cells. Mol Biol Cell 18:781-794. Oriolo, A.S., Wald, F.A., Ramsauer, V.P., and Salas, P.J. 2007. Intermediate filaments: a role in epithelial polarity. Exp Cell Res 313:2255-2264. Pino, V., Ramsauer, V.P., Salas, P., Carothers Carraway, C.A., and Carraway, K.L. 2006. Membrane mucin Muc4 induces density-dependent changes in ERK activation in mammary epithelial and tumor cells: role in reversal of contact inhibition. J Biol Chem 281:29411-29420. Ramsauer, V.P., Pino, V., Farooq, A., Carothers Carraway, C.A., Salas, P.J., and Carraway, K.L. 2006. Muc4-ErbB2 complex formation and signaling in polarized CACO-2 epithelial cells indicate that Muc4 acts as an unorthodox ligand for ErbB2. Mol Biol Cell 17:2931-2941. Wald, F.A., Oriolo, A.S., Casanova, M.L., and Salas, P.J. 2005. Intermediate filaments interact with dormant ezrin in intestinal epithelial cells. Mol Biol Cell 16:4096-4107. Ameen, N.A., Marino, C., and Salas, P.J. 2003. cAMP-dependent exocytosis and vesicle traffic regulate CFTR and fluid transport in rat jejunum in vivo. Am J Physiol Cell Physiol 284:C429-438. Ramsauer, V.P., Carraway, C.A., Salas, P.J., and Carraway, K.L. 2003. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, translocates ErbB2 to the apical surface in polarized epithelial cells. J Biol Chem 278:30142-30147. Figueroa, Y., Wald, F.A., and Salas, P.J. 2002. p34cdc2-mediated phosphorylation mobilizes microtubule-organizing centers from the apical intermediate filament scaffold in CACO-2 epithelial cells. J Biol Chem 277:37848-37854. Wald, F.A., Figueroa, Y., Oriolo, A.S., and Salas, P.J. 2003. Membrane repolarization is delayed in proximal tubules after ischemia-reperfusion: possible role of microtubule-organizing centers. Am J Physiol Renal Physiol 285:F230-240. Yang X., Salas P.J., Pham T.V., Gelband H., Wasserlauf B.J., Smets M.J.D., Myerburg R.J., Hoffman B.F. and Bassett A.L. 2002. Cytoskeletal actin microfilaments and the transient outward potassium current in hypertrophied rat ventriculocytes. J. Physiol 1(541):411-21.
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