Christopher M. Waters, Ph.D.


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Professor and Vice Chair
Email: cwaters2@uthsc.edu
Phone: 901-448-5799
Fax: 901-448-7126
Full CV

Education

B.S.E., Chemical Engineering, University of Tennessee at Chattanooga, 1985
M.S., Biomedical Engineering, University of Miami, FL, 1987
Ph.D., Biomedical Engineering, Vanderbilt University, 1991
Post Doc, Biomedical Engineering, Vanderbilt University, 1991-1992


Research Interests

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My laboratory focuses on mechanobiology and acute lung injury. 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. 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 in injured lungs induces mechanical stresses that increase injury to the lung epithelium, stimulate inflammatory responses, and decrease repair mechanisms.

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We are focusing on the mechanisms by which mechanical forces contribute to lung injury, 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, cytokine secretion, and regional variations in cellular tension. In addition we are examining lung injury in vivo and the effects of exposure to high levels of oxygen (hyperoxia). 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.

Current Techniques:

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  • Isolation and culture of airway and alveolar epithelial cells, lung vascular endothelial cells, and brain microvascular endothelial cells.
  • Application of fluid shear stress to cells - flow chambers, cell columns.
  • Application of cyclic mechanical strain to cells.
  • Evaluation of permeability of cell monolayers - cell column (on line), transwell culture.
  • Transepithelial electrical resistance measurements (including the ECIS system).
  • Western analysis to measure cytoskeletal and focal adhesion levels.
  • Confocal fluorescence microscopy to visualize cell cytoskeleton (f-actin, microtubules), focal adhesions, integrins, junctional assembly.
  • Atomic force microscopy to determine stress distribution in wounded cells.
  • Wound healing assays.
  • Spectrophotometry and fluorescence microscopy to measure reactive oxygen species production.
  • Pull down assays to measure Rho GTPase activity.
  • Adenoviral and lentiviral expression systems to evaluate signaling pathways.
  • Mechanically ventilated mice and rats; evaluation of lung injury and measurement of lung mechanics (resistance and compliance).

Research Support

Principal Investigator: "Mechanotransduction in Acute Lung Injury," National Institutes of Health (R01 HL094366-01); 04/01/09-03/31/13; no cost extension until 03/31/14.

Mentor: "The role of 2-pore domain potassium channels in acute lung injury," K08, National Institutes of Health, Dr. Andreas Schwingshackl, P.I.; 02/01/14-01/31/18.

Mentor: "The role of the 2-pore domain potassium channel Trek-1 in acute lung injury," American Lung Association, Dr. Andreas Schwingshackl, P.I.; 07/01/13-06/30/15

Pending

Principal Investigator: "Mechanotransduction in Acute Lung Injury," National Institutes of Health, competitive renewal, 13th percentile.

Principal Investigator: "CXCR4 signaling in lung epithelial repair," National Institutes of Health, 5th percentile.

Mentor: "TNF-a Induced Increase in Alveolar Epithelial Cell Stiffness and Lung Injury," K01, National Institutes of Health, Dr. Esra Roan, P.I.


Selected Publications

  1. Desai, L.P., S.E. Sinclair, K.E. Chapman, A. Hassid, and C.M. Waters. High tidal volume mechanical ventilation with hyperoxia alters focal adhesions of alveolar type II cells, Am. J. Physiol. Lung Cell. Mol. Physiol. 293: L769-L778, 2007. PMID: 17601798
  2. Sinclair, S.E., R.C. Molthen, S.A. Hayworth, C.A. Dawson, and C.M. Waters. Airways strain during mechanical ventilation in an intact animal model, Am J. Resp. Crit. Care Med. 176: 786-794, 2007. PMID: 17626911
  3. Wagh, A.A., E. Roan, K.E. Chapman, L.P. Desai, D. Rendon, E.C. Eckstein, and C.M. Waters. Localized elasticity measured in epithelial cells migrating at a wound edge using atomic force microscopy, Am. J. Physiol. Lung Cell. Mol. Physiol. 295: L54-L60, 2008. PMID: 18487359
  4. Narang, V.S., C. Fraga, N. Kumar, J. Shen, S. Throm, C.F. Stewart, and C.M. Waters. Dexamethasone increases expression and activity of multi-drug resistance transporters at the rat blood-brain barrier, Am. J. Physiol. Cell Physiol. 295: C440-C450, 2008. PMID: 18524938
  5. Desai, L.P., S.R. White, and C.M. Waters. Mechanical stretch decreases FAK phosphorylation and reduces cell migration through loss of JIP3-induced JNK phosphorylation, Am. J. Physiol. Lung Cell. Mol. Physiol. 297: L520-529, 2009. PMID: 19574423
  6. Desai, L.P., S.R. White, and C.M. Waters. Cyclic mechanical stretch decreases cell migration by inhibiting phosphatidylinositol 3-kinase- and focal adhesion kinase-mediated JNK1 activation, J. Biol. Chem. 285: 4511-4519, 2010. JBC paper of the week. PMID: 20018857
  7. Crosby, L.M., and C.M. Waters. Epithelial repair mechanisms in the lung, Am. J. Physiol. Lung Cell. Mol. Physiol. 298: L715-L731, 2010. PMID: 20363851
  8. Carcaboso, A.M., M.A. Elmeliegy, J. Shen, S.J. Juel, Z.M. Zhang, C. Calabrese, L. Tracey, C.M. Waters, and C.F. Stewart. Tyrosine kinase inhibitor gefitinib enhances topotecan penetration of gliomas, Canc. Res. 70: 4499-4508, 2010. PMID: 20460504
  9. Makena, P.S., C.L. Luellen, L. Balazs, M.C. Ghosh, K. Parthasarathi, C.M. Waters, S.E. Sinclair. Pre-exposure to hyperoxia causes increased lung injury and epithelial apoptosis in mice ventilated with high tidal volumes, Am. J. Physiol. Lung Cell. Mol. Physiol. 299: L711-L719, 2010. PMID: 20833778.
  10. Crosby, L.M., C. Luellen, Z. Zhang, L.L. Tague, S.E. Sinclair, and C.M. Waters. The balance of life and death in alveolar epithelial type II cells: proliferation, apoptosis, and the effects of cyclic stretch on wound healing, Am. J. Physiol. Lung Cell. Mol. Physiol. 301: L536-L546, 2011. PMID: 21724858.
  11. Makena, P.S., V.K. Gorantla, M.C. Ghosh, L. Bezwada, L. Balazs, C. Luellen, K. Parthasarathi, C.M. Waters, and S.E. Sinclair. Lung injury caused by high tidal volume mechanical ventilation and hyperoxia is dependent upon oxidant-mediated c-Jun NH2-terminal kinase (JNK) activation, J. Appl. Physiol. 111: 1467-1476, 2011. PMID: 21799126.
  12. Roan, E., and C.M. Waters. What do we know about mechanical strain in lung alveoli? Am. J. Physiol. Lung Cell. Mol. Physiol. 301: L625-L635, 2011. PMID: 21873445.
  13. Schwingshackl, A., B. Teng, M. Ghosh, A.N. West, P. Makena, V. Gorantla, S. Sinclair, and C.M. Waters. Regulation and function of the two-pore domain (K2P) potassium channel Trek-1 in alveolar epithelial cells, Am. J. Physiol. Lung Cell. Mol. Physiol. 302: L93-L102, 2012. PMID: 21949155.
  14. Waters, C.M., E. Roan, and D. Navajas. Mechanobiology in lung epithelial cells: Measurements, Perturbations, and Responses, Comprehensive Physiology 2: 1-29, 2012.
  15. Makena, P.S., V.K. Gorantla, M.C. Ghosh, L. Bezawada, L. Balazs, C. Luellen, K. Parthasarathi, C.M. Waters, and S.E. Sinclair. Deletion of apoptosis signal regulating kinase-1 prevents ventilator-induced lung injury in mice, Am. J. Resp. Cell Mol. Biol. 46: 461-469, 2012. PMID: 22052879.
  16. Ghosh, M.C., P.S. Makena, V. Gorantla, S.E. Sinclair, and C.M. Waters. CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2 (MMP-2), Am. J. Physiol. Lung Cell. Mol. Physiol. 302: L846-L856, 2012. PMID: 22345572.
  17. Roan, E., K. Wilhelm, A. Bada, P.S. Makena, V.K. Gorantla, S.E. Sinclair, and C.M. Waters. Hyperoxia alters the mechanical properties of alveolar epithelial cells, Am. J. Physiol. Lung Cell. Mol. Physiol. 302: L1235-L1241, 2012. PMID: 22467640.
  18. Schwingshackl, A., B. Teng, M. Ghosh, K.G. Lim, G. Tigyi, D. Narayanan, J. Jaggar, and C.M. Waters. Regulation of interleukin-6 secretion by the two-pore-domain potassium (K2P) channel Trek-1 in alveolar epithelial cells, Am. J. Physiol. Lung Cell. Mol. Physiol. 304: L276-L86, 2013. PMID: 23275623.
  19. Ghosh, M.C., V. Gorantla, P.S. Makena, C. Luellen, S.E. Sinclair, and C.M. Waters. Insulin like growth factor-1 stimulates differentiation of ATII cells to ATI-like cells through activation of Wnt5a, Am. J. Physiol. Lung Cell. Mol. Physiol. 305: L222-L228, 2013.
  20. Schwingshackl, A., B. Teng, M. Ghosh, and C.M. Waters. Regulation of MCP-1 secretion by Trek-1 in alveolar epithelial cells, Am. J. Translational Res. 5(5): 530-542, 2013.
  21. Wilhelm, K., E. Roan, M. Ghosh, K. Parthasarathi, and C.M. Waters. Hyperoxia increases the elastic modulus of alveolar epithelial cells through Rho kinase, FEBS J. 281: 957-969, 2013.
  22. Roan, E., C.M. Waters, B. Teng, M. Ghosh, and A. Schwingshackl. The 2-pore domain potassium channel TREK-1 regulates stretch-induced detachment of alveolar epithelial cells, PLOS One 9(2): e89429, 2014.
  23. Samak, G., R. Gangwar, L.M. Crosby, L.P. Desai, K. Wilhelm, C.M. Waters, R.K. Rao. Cyclic stretch disrupts apical junctional complexes in Caco-2 cell monolayers by a c-Jun N-terminal kinase-2, c-Src and myosin light chain kinase-dependent mechanism, Am. J. Physiol. Gastrointest. Liver Physiol. 306 (11): G947-G958, 2014.
  24. Schwingshackl, A., B. Teng, P. Makena, M. Ghosh, S.E. Sinclair, C. Luellen, L. Balasz, C. Rovnaghi, R.M. Bryan, E. Lloyd, E. Fitzpatrick, J.S. Saravia, S. Cormier, and C.M. Waters. Deficiency of the two-pore potassium (K2P) channel Trek-1 promotes hyperoxia-induced lung injury, in press, Crit. Care Med.