Robert Tarran , PhD
Research Assistant Professor
Joint Appointment in Medicine

Education:

B.Sc. University of Leeds, 1994
Ph.D., University of Newcastle-upon-Tyne, 1998

Signal transduction and the regulation of ion transport in airway epithelia

	Figure 1
	click image for larger view and legend

It has recently been shown that a critical component of airways innate defense is the thin (7 µm) liquid layer lining airway surfaces, the periciliary liquid (PCL), that provides a low viscosity solution for ciliary beating and acts a lubricant layer for mucus transport. Normal airways appear to be able to sense the PCL volume and adjust ion channel activity accordingly by unknown mechanisms. A proposed model for ASL volume regulation is shown in Fig. 1.

Apical membrane ion channel activity controls the amount of salt (and water) on airway surfaces and hence, PCL volume and mucus hydration levels. It has recently been proposed that the initiating event in CF lung disease is depletion of the PCL due to abnormal ion channel activity (i.e. a lack of CFTR), which causes dehydrated mucus to adhere to airway surfaces, preventing it from being cleared (Fig. 2), causing increased bacterial infections.

Figure 2
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The long term goal of this laboratory is to understand how homeostasis of PCL volume occurs in airway epithelia under normal and pathophysiological conditions. Currently, research in the Tarran lab is focused on three main areas, listed below, and we utilize cell biological and biochemical techniques coupled with in vivo translational approaches to address these questions:

	Figure 3
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1. Regulation of epithelial cell function by the extracellular environment: We have hypothesized that nucleotides, proteases and other molecules contained in the ASL (ATP for example) can regulate airway ion transport. Fig. 3 depicts cystic fibrosis airway cells that have lost the ability to regulate ASL volume following infection with GFP-labeled viruses that inhibit intracellular Ca²⁺ signaling by depleting extracellular ATP.
   
   
2. Gender differences in cystic fibrosis lung disease: Females suffer more severely with cystic fibrosis than their male counterparts, resulting in a significantly shorter lifespan. This gender difference becomes apparent after puberty. Accordingly, we are currently investigating whether estrogens affect Ca²⁺ signaling and ASL

   Figure 4
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   homeostasis. Fig. 4 shows an example of simultaneous Fura-2 imaging (as a marker of intracellular Ca²⁺) and a fusion protein of Estrogen Receptor α (ER α) conjugated to orange fluorescent protein (mOr).
   
   
3. The effects of cigarette smoke on epithelial airway ion transport: Similar to CF, long term tobacco exposure also results in chronic mucus accumulation. We have found that acute tobacco exposure causes a loss of CFTR from the plasma membrane (Fig. 5) and are currently investigating this phenomenon.

Figure 5

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Techniques used in our lab:

Ca²⁺ imaging
Confocal microscopy
Electrophysiology (In vivo nasal potential difference measurements, microelectrodes & Ussing chambers)
Fluorescence resonance energy transfer (FRET)
Mass Spectrometry
Molecular Biology & Real Time (q)PCR
Tissue culture
Western Blot

Recent Publications

Chambers LA, Rollins BM & Tarran R. (2007) Liquid movement across the surface epithelium of large airways. Respiratory Physiology. In press.

Tarran R, Trout L, Donaldson SH, Boucher RC. (2006) Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J Gen Physiol. 127(5):591-604.

Donaldson SH, Bennett WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. (2006) Mucus clearance and lung function in cystic fibrosis with hypertonic saline. N Engl J Med. 354(3):241-50.

Tarran R, Button B, Picher M, Paradiso AM, Ribeiro CM, Lazarowski ER, Zhang L, Collins PL, Pickles RJ, Fredberg JJ, Boucher RC. (2005) Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections. J. Biol. Chem. 280(42):35751-9.

Thelin WR, Kesimer M, Tarran R, Kreda SM, Grubb BR, Sheehan JK, Stutts MJ, Milgram SL. (2005) The cystic fibrosis transmembrane conductance regulator is regulated by a direct interaction with the protein phosphatase 2A. J Biol Chem. 2005 Dec 16;280(50):41512-20.

Lazarowski ER, Tarran R, Grubb BR, van Heusden CA , Okada S, Boucher RC. (2004) Nucleotide release provides a mechanism for airway surface liquid homeostasis. J. Biol. Chem. 279(35):36855-64

Tarran, R. (2004) Regulation of Airway Surface Liquid Volume and Mucus Transport by Active Ion Transport. Proceedings of the American Thoracic Society. 1: 42–46.

G.M. Roomans, I. Kozlova, H. Nilsson, V. Vanthanouvong, B. Button & R. Tarran. (2004) Measurements of airway surface liquid height and mucus transport by fluorescence microscopy, and of ion composition by X-ray microanalysis. Journal of Cystic Fibrosis. S2, 135-9.

Davidson, D.J., Gray, M.A., Kilanowski, F.M., Tarran, R. , Randell, S.H., Sheppard, D.N., Argent, B.E. & Dorin, J.R. (2004) Murine epithelial cells: isolation and culture. Journal of Cystic Fibrosis. S2, 59-62.

Tarran, R. & Boucher, R.C. (2002) Thin-film measurements of airway surface liquid volume/composition and mucus transport rates in vitro . In: Methods in Molecular Medicine. (Skach, W.R. ed.) (Humana Press , NJ). 70, 479-92.

Tarran, R., Lowen, M., Gray, M.A., Argent, B.E., Boucher, R.C., & Gabriel, S.E. (2002) Regulation of murine airway surface liquid volume by CFTR and Ca²⁺-activated Cl^- conductances. Journal of General Physiology, 120, 3-15.

*Tarran, R., *Worlitzsch, D., *Ulrich, M., Schwab, U., Cekici, A, Meyer, K.C., Birrer, P., Bellon, G., Ramphal, R., Berger, J., Weiss, T., Yankaskas, J.R., Botzenhart, K, Boucher, R.C. & Doring, G. (2002) Effects of reduced mucus oxygen concentration in airway Pseudomonas aeruginosa infections of cystic fibrosis patients. Journal of Clinical Investigation. 109, 317-325. (*Joint First Authorship).

Caldwell, R.A, Grubb, B.R., Tarran, R., Boucher, R.C., Knowles, M.R., Barker, P.M. (2002) In Vivo Airway Surface Liquid Cl^- Analysis with Solid-state Electrodes. Journal of General Physiology, 119 (1) ,3-14.

Huang, P., Lazarowski, E.R., Tarran, R., Milgram, S., Boucher, R.C. & Stutts, M.J. (2001) Compartmentalized autocrine signalling to cystic fibrosis transmembrane conductance regulator at the apical membrane of airway epithelial cells. P.N.A.S. 98(24), 14120-5.

Tarran, R., Grubb, B.R., Gatzy, J.T., Davis , C.W. & Boucher, R.C. (2001) Relative roles of passive surface forces and active ion transport in the modulation of airway surface liquid volume and composition. Journal of General Physiology, 118(2), 223-236.

Tarran, R., Grubb, B.R., Parsons, D., Picher, M., Hirsh, A.J., Davis, C.W. & Boucher, R.C. (2001) The CF salt controversy: Implications for therapies designed to correct abnormalities in CF airway surface liquid based on in vivo and in vitro studies. Molecular Cell, 8(1), 149-158.

Tarran, R., Argent, B.E. & Gray, M.A. (2000) Regulation of a hyperpolarization-activated chloride current in murine respiratory ciliated cells. Journal of Physiology, 524 (2), 353-364.

Matsui, H., Davis , C.W., Tarran, R. & Boucher, R.C. (2000) Osmotic water permeability of well-differentiated normal and CF epithelial cell cultures: cellular and paracellular paths as measured by confocal microscopy. Journal of Clinical Investigation, 105, 1419-1427.

Becq, F., Mette, Y., Gray, M.A., Galietta, L.J.V., Dormer, R.L., Merten, M., Métayé, T., Chapp, V., Marvingt-Mounir, C., Zegarra-Moran, O., Tarran, R., Bulteau, L., Dérand, R., Pereir, M.C., McPherson, M.A., Rogierb, C., Joffreb, M., Argent, B.E. Sarrouil, D., Kammouni, W., Figarella, C., Verrier, B., Gola, M. & Vierfond J.M. (1999) Development of substituted benzo[c]quinolizinium compounds as novel activators of the cystic fibrosis chloride channel. Journal of Biological Chemistry, 274 (39), 27415-27425.

*Tarran, R., *Matsui, H., *Grubb, B.R., Randell, S.H., Gatzy, J.T., Davis, C.W. & Boucher, R.C. (1998) Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell, 95, 1005-1015. (*Joint First Authorship).

Tarran, R., Gray, M.A., Evans, M.J., Colledge, W.H., Ratcliff, R. & Argent, B.E. (1998) Basal Cl^- conductances in murine airway epithelia: Modulation by CFTR. American Journal of Physiology, 274 (43), C904-C913.