CHRISTOPHER M. WATERS, Ph.D., M.S., B.S.E.

Professor and Vice Chair
Physiology
 
Professor
Medicine-Pulmonary

Office: 201 Nash Research Building
Tel: (901) 448-5799
cwaters2@uthsc.edu

Education

  • PostDoc, Vanderbilt University, Biomedical Engineering
  • Ph.D., Vanderbilt University, Nashville, TN, Biomedical Engineering
  • Ph.D., Vanderbilt University, Biomedical Engineering
  • M.S., University of Miami (FL), Biomedical Engineering
  • M.S., University of Miami (FL), Biomedical Engineering
  • B.S.E., University of Tennessee at Chattanooga, Chemical Engineering

Research interest/specialty

My laboratory focuses on two main areas: (1) acute lung injury, and (2) drug transport in the brain.

Research keywords

acute respiratory distress syndrome (ARDS), blood-cerebrospinal fluid (CSF), blood-cerebrospinal barrier (BCB), blood-brain barrier (BBB), P-glycoprotein (P-gp), ATP-binding cassette, CNS tumors, multi-drug resistance protein 4 (MRP4), breast cancer resistance protein (BCRP or ABCG2),

Research interest/specialty

My laboratory focuses on two main areas: (1) acute lung injury, and (2) drug transport in the brain.

Research keywords

acute respiratory distress syndrome (ARDS), blood-cerebrospinal fluid (CSF), blood-cerebrospinal barrier (BCB), blood-brain barrier (BBB), P-glycoprotein (P-gp), ATP-binding cassette, CNS tumors, multi-drug resistance protein 4 (MRP4), breast cancer resistance protein (BCRP or ABCG2),

Research description

(1) Patients with acute respiratory distress syndrome (ARDS) are placed on mechanical ventilators to improve oxygenation, but the ventilator may cause additional injury to the lungs due to either overdistention or airway collapse and reopening. Recent clinical trials have demonstrated a substantial reduction in mortality in ARDS patients when ventilation strategies are used that reduce overdistention (lower tidal volumes) and minimize airway collapse and reopening (positive end expiratory pressure). The lung is a mechanically dynamic organ, and cells in the lung are subjected to shear stress due to fluid flow, tensile and compressive forces due to respiratory motion, and normal forces due to vascular or airway pressure. High tidal volume mechanical ventilation induces mechanical stresses that increase injury to the lung epithelium, stimulate inflammatory responses, and decrease repair mechanisms. We are focusing on the mechanisms by which mechanical forces inhibit wound healing of lung epithelial cells and stimulate inflammation. We are examining cell migration and wound healing, Rho GTPase signaling, cytoskeletal remodeling, stimulation of reactive oxygen species, and regional variations in cellular tension. In addition we are examining lung injury in vivo. My research seeks to identify the levels of mechanical forces and the types of lung injury that cells experience in vivo, to develop in vitro models to evaluate cellular responses, and to identify mechanisms by which mechanical forces are transduced into biological signals. (2) Tightly regulated cellular barriers limit delivery of pharmacological agents to children with primary tumors in the central nervous system (CNS). The physiological regulation of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCB) and the specificity for excluding or allowing drug transport are not well understood. Camptothecin analogs such as topotecan and irinotecan are used to treat children with primary CNS tumors, but the CNS distribution of these drugs is widely different. The discovery of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transport proteins has challenged the view that only passive diffusion and physicochemical properties control drug distribution. In collaboration with Dr. Clinton Stewart at St. Jude Children?s Research Hospital we are testing the that the distribution of camptothecin analogs between the blood, brain tissue, and the CSF is largely controlled by drug efflux transporters, including P-pg, multi-drug resistance protein 4 (MRP4), and the breast cancer resistance protein (BCRP or ABCG2). We seek to understand how drug distribution is controlled at the BBB and the BCB. We are developing tissue engineered models of the BBB and BCB to investigate drug transport in vitro. Cells transfected with different ABC transporters are used to determine the specificity of transporters for camptothecin analogs. Mathematical models are being used to evaluate transport parameters from experimental data. We are also examing the mechanisms of camptothecin analog transport in vivo using immunohistochemistry to determine the anatomical distribution of ABC transporters, and microdialysis measurements of brain and CSF drug concentrations in knockout mice deficient in MRP4 and ABCG2. Our long-term goals are to understand the regulation of drug transport in the CNS, to develop in vitro and in vivo models to test camptothecin analogs, and to define and quantify parameters that can be used to compare drugs and ultimately improve therapy for children with primary CNS tumors.

Publications

  1. Desai, LP, Chapman, KE, Waters, CM. Mechanical stretch decreases migration of alveolar epithelial cells through mechanisms involving Rac1 and Tiam1. Am J Physiol Lung Cell Mol Physiol, 295 (5), L958-65, 2008.
  2. Narang, VS, Fraga, C, Kumar, N, Shen, J, Throm, S, Stewart, CF, Waters, CM. Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. Am J Physiol Cell Physiol, 295 (2), C440-50, 2008.
  3. Wagh, AA, Roan, E, Chapman, KE, Desai, LP, Rendon, DA, Eckstein, EC, Waters, CM. Localized elasticity measured in epithelial cells migrating at a wound edge using atomic force microscopy. Am J Physiol Lung Cell Mol Physiol, 295 (1), L54-60, 2008.
  4. Xi, Q, Adebiyi, A, Zhao, G, Chapman, KE, Waters, CM, Hassid, A, Jaggar, JH. IP3 Constricts Cerebral Arteries via IP3 Receptor-Mediated TRPC3 Channel Activation and Independently of Sarcoplasmic Reticulum Ca2+ Release. Circ Res, 2008.
  5. Sinclair, SE, Molthen, RC, Haworth, ST, Dawson, CA, Waters, CM. Airway strain during mechanical ventilation in an intact animal model. Am J Respir Crit Care Med, 176 (8), 786-94, 2007.
  6. Kumar, N, Mishra, J, Narang, VS, Waters, CM. Janus kinase 3 regulates interleukin 2-induced mucosal wound repair through tyrosine phosphorylation of villin. J Biol Chem, 282 (42), 30341-5, 2007.
  7. Desai, LP, Sinclair, SE, Chapman, KE, Hassid, A, Waters, CM. High tidal volume mechanical ventilation with hyperoxia alters alveolar type II cell adhesion. Am J Physiol Lung Cell Mol Physiol, 293 (3), L769-78, 2007.
  8. Zhuang, Y, Fraga, CH, Hubbard, KE, Hagedorn, N, Panetta, JC, Waters, CM, Stewart, CF. Topotecan central nervous system penetration is altered by a tyrosine kinase inhibitor. Cancer Res, 66 (23), 11305-13, 2006.
  9. Motl, S, Zhuang, Y, Waters, CM, Stewart, CF. Pharmacokinetic considerations in the treatment of CNS tumours. Clin Pharmacokinet, 45 (9), 871-903, 2006.
  10. Ceacareanu, AC, Ceacareanu, B, Zhuang, D, Chang, Y, Ray, RM, Desai, L, Chapman, KE, Waters, CM, Hassid, A. Nitric oxide attenuates IGF-I-induced aortic smooth muscle cell motility by decreasing Rac1 activity: essential role of PTP-PEST and p130cas. Am J Physiol Cell Physiol, 290 (4), C1263-70, 2006.
  11. Geiger, R.C., Waters, C.M.. KGF prevents DNA damage in ARPE-19 cells. Investigative Opthamalogy & Visual Science, 46, 3435-3441, 2005.
  12. Chapman, K.E., S.E. Sinclair, A. Hassid, D. Zhuang, L.P. Desai, and C.M. Waters. Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells. American Journal of Physiology: Lung Cellular Molecular Physiology, 289, 834-841, 2005.
  13. Desai, LP, Aryal, AM, Ceacareanu, B, Hassid, A, Waters, CM. RhoA and Rac1 are both required for efficient wound closure of airway epithelial cells. Am J Physiol Lung Cell Mol Physiol, 287 (6), L1134-44, 2004.
  14. Ahmed, A, Waters, CM, Leffler, CW, Jaggar, JH. Ionic mechanisms mediating the myogenic response in newborn porcine cerebral arteries. Am J Physiol Heart Circ Physiol, 287 (5), H2061-9, 2004.
  15. Tomar, A, Wang, Y, Kumar, N, George, S, Ceacareanu, B, Hassid, A, Chapman, KE, Aryal, AM, Waters, CM, Khurana, S. Regulation of cell motility by tyrosine phosphorylated villin. Mol Biol Cell, 15 (11), 4807-17, 2004.
  16. Leggas, M, Zhuang, Y, Welden, J, Self, Z, Waters, CM, Stewart, CF. Microbore HPLC method with online microdialysis for measurement of topotecan lactone and carboxylate in murine CSF. J Pharm Sci, 93 (9), 2284-95, 2004.
  17. Zhuang, D, Ceacareanu, AC, Lin, Y, Ceacareanu, B, Dixit, M, Chapman, KE, Waters, CM, Rao, GN, Hassid, A. Nitric oxide attenuates insulin- or IGF-I-stimulated aortic smooth muscle cell motility by decreasing H2O2 levels: essential role of cGMP. Am J Physiol Heart Circ Physiol, 286 (6), H2103-12, 2004.
  18. Savla, U., L.E. Olson, and C.M. Waters. Mathematical modeling of airway epithelial wound closure during cyclic mechanical strain. Journal of Applied Physiology, 96, 566-574, 2004.
  19. Waters, C.M.. Reactive oxygen species in mechanotransduction, Editorial comment. American Journal of Physiology: Lung Cellular Molecular Physiology, 287, L484-L485, 2004.
  20. Boardman, K.C., W.M. Miller, and C.M. Waters. Actin redistribution in response to hydrogen peroxide in airway epithelial cells. Journal of Cellular Physiology, 199, 57-66, 2004.
  21. Leffler, CW, Balabanova, L, Fedinec, AL, Waters, CM, Parfenova, H. Mechanism of glutamate stimulation of CO production in cerebral microvessels. Am J Physiol Heart Circ Physiol, 285 (1), H74-80, 2003.
  22. Waters, CM, Sporn, PH, Liu, M, Fredberg, JJ. Cellular biomechanics in the lung. Am J Physiol Lung Cell Mol Physiol, 283 (3), L503-9, 2002.
  23. Chapman, K.E., C.M. Waters, and W.M. Miller. Continuous exposure of airway epithelial cells to hydrogen peroxide: protection by KGF. Journal of Cellular Physiology, 192, 71-80, 2002.
  24. Haber,R., J.B. Grotberg, M.R. Glucksberg, G. Miserocci, D. Venturoli, M. Del Fabbro and C.M. Waters. Steady_state pleural fluid flow and the effects of lung buoyancy. Journal of Biomechanic Engineering, 123, 485-492, 2001.
  25. Waters, C.M., M.R. Glucksberg, E.P. Lautenschlager, C.-W. Lee, R.M. VanMatre, R.J. Warp, U. Salva, K.E. Healy, B. Moran, D.G. Castner, and J.P. Bearinger. A system to impose prescribed homogeneous strains on cultured cells. Journal of Applied Physiology, 91, 1600-1610, 2001.
  26. Salva, U., H.J. Appel, P.H.S. Sporn, and C.M. Waters. Prostaglandin E2 regulates wound closure of airway epithelial cells. American Journal of Physiology: Lung Cellular Molecular Physiology, 280, L421-L431, 2001.
  27. Waters, C.M., T.C. Krejcie, and M.A. Avram. Facilitated uptake of fentanyl, but not alfentanil, by human pulmonary endothelial cells. Anesthesiology, 93, 825-831, 2000.
  28. Albuquerque, M.L., C.M. Waters, U. Salva, H.W. Schnaper, and A. Flozak. Shear stress enhances human endothelial cell wound closure. American Journal of Physiology: Heart Circulation Physiology, 279, H293-H302, 2000.
  29. Waters, C.M., K. Ridge, G. Sunio, K. Venetsanou, and J.I. Sznajder. Mechanical stretching of alveolar epithelial cells increases Na,K-ATPase activity. Journal of Applied Physiology, 87, 715-721, 1999.
  30. Waters, C.M., M.A. Avram, T.C. Krejcie, and T.K. Henthorn. Uptake of fentanyl in pulmonary endothelium. Journal of Pharmacology and Experimental Therapeutics, 288, 157-163, 1999.
  31. Gillis, P., U. Salva, O.V. Volpert, B. Jimenez, C.M. Waters. Keratinocyte growth factor induces angiogenesis and protects endothelial barrier function. Journal of Cell Science, 112, 2049-2057, 1999.
  32. Waters, C.M., and U. Salva. Keratinocyte growth factor accelerates wound closure in airway epithelium during cyclic mechanical strain. Journal of Cellular Physiology, 181, 424-432, 1999.
  33. Salva, U and C.M. Waters. Mechanical strain inhibits repair of airway epithelium in vitro. American Journal of Physiology, 274, L883-L892, 1998.
  34. Salva, U. and C.M. Waters. Barrier function of airway epithelium: effects of radiation and protection by keratinocyte growth factor. Radiation Research, 150, 195-203, 1998.
  35. Wagers, A.J., C.M. Waters, L.M. Stoolman, and G.S. Kansas. Interleukin 12 and interleukin 4 control T cell adhesion to endothelial selectins through opposite effects on a 1,3-fucosyltransferase VIi gene expression. Journal of Experimental Medicine, 188, 2225-2231, 1998.
  36. Salva, U., P.H.S. Sporn, and C.M. Waters. Cyclic stretch of airway epithelum inhibits prostanoid synthesis. American Journal of Physiology, 273, L1013-1019, 1997.
  37. Rezania, A., C.H. Thomas, A.B. Branger, C.M. Waters, and K.E. Healy. The detachment strength and morphology of bone cells contacting materials modified with a peptide derived form bone sialoprotein. Journal of Biomedical Materials Research, 37, 9-19, 1997.
  38. Waters, C.M., U. Salva, and R. Pancos. Keratinocyte growth factor prevents hydrogen peroxide-induced increases in airway epithelial cell permeability. American Journal of Physiology, 272, L681-L689, 1997.
  39. Waters, C.M., J. Chang, M.R. Glucksburg, N. DePaola, and J.B. Grotberg. Mechanical forces after growth factor release by pleural mesothelial cells. American Journal of Physiology, 272, L552-L557, 1997.
  40. Waters, C.M.. Flow-induced modulation of the permeability of endothelial cells cultured on microcarrier beads. Journal of Celluar Physiology, 168, 403-411, 1996.
  41. Waters,C.M., J. Taylor, A. Molteni, and W.F. Ward. Dose-response effects of radiation on endothelial cell permeability in culture. Radiation Research, 146, 321-328, 1996.
  42. Waters, C.M., M.R. Glucksberg, N. DePaola, J. Chang, and J.B. Grotberg. Shear stress alters pleural mesothelial cell permeability in culture. Journal of Applied Physiology, 81, 448-458, 1996.
  43. Sorkin, A., C.M. Waters, K.A. Overholser, and G. Carpenter. Multiple autophosphorylation site mutations of the epidermal growth factor receptor: analysis of kinase activity and endocytosis. J. Biology Chemistry, 266, 8355-8362, 1991.
  44. Waters, C.M., K.O.Oberg, G. Carpenter, and K.A. Overholser. Rate constants for binding, dissociation, and internalization of epidermal growth factor: effect of receptor occupancy and ligand concentration. Biochemistry, 29, 3563-3569, 1990.