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Center for Human Genomics at Wake Forest University School of Medicine

Raymond Penn, PhD
Associate Professor of Medicine

1976-1980 University of Pennsylvania - B.A., History
1979-1980 University of Pennsylvania - M.S. Ed., Education
1984-1988 Temple University School of Medicine - Ph.D., Physiology

Research Interests

The major focus of my research is to identify cellular and molecular mechanisms by which G protein-coupled receptors (GPCRs) mediate important functions in airway cells. GPCR signaling regulates contractile function, synthesis and release of autocrine factors, and cell growth in various airway cells, including airway smooth muscle (ASM), airway epithelium, lung fibroblasts, and T lymphocytes. Aberrant GPCR signaling or exaggerated presentation of GPCR stimuli can promote ASM hypercontractility, airway remodeling, and airway cell hyperplasia/hypertrophy, all of which contribute to the pathogenesis of asthma.

The long range goal of my research is to elucidate regulatory features of signaling in airway cells that may be targeted (either pharmacologically or via gene therapy) in the management of airway diseases. Toward this end my lab has established novel approaches in the application of molecular biology techniques in primary cultures of airway cells. For example, we have generated, through the use of fluorescence-activated cell sorting, homogeneous populations of ASM cells that express green fluorescent protein (GFP) chimeras of key signaling intermediates. Sorting of cells expressing GFP chimeras overcomes limitations imposed by low transfection efficiency of primary cell cultures, thus enabling us to examine the role of GPCR expression (Mundell et al. Am J Respir Cell Mol Biol, 2001) as well as disrupted GPCR-G protein coupling (Penn et al., J Biol Chem, 2001) on receptor signaling and trafficking outcomes. These studies are the first of their kind in primary airway cells and represent a significant advancement in the study of airway cell biology. Importantly, this methodology can be applied to study myriad signaling events and their relevance to virtually any airway cell function. Other ongoing studies include: 1) defining the mechanisms by which receptor tyrosine kinase activation (by numerous growth factors) synergizes with signals from GPCRs to augment ASM growth; 2) delineating pathways involved in cytokine effects on ASM chemokine and adhesion molecule synthesis; 3) identifying mechanisms by which contractile and inflammatory agents sensitize adenylyl cyclase and thereby mitigate the effect of GPCR desensitization on cAMP-dependent signaling; 4) characterizing GPCR signaling in human T cells with emphasis on understanding how T cell proliferation and maturation is affect by beta-agonists, adenosine, and PGE2.; and 5) establishing retrovirus and lentivirus infection approaches for high efficiency recombinant protein expression in primary airway cells.

Publications

Peer reviewed journal articles

Billington CK, Penn RB. Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res. 2003 Mar 14;4(1):2.

Pascual RM, Awsare BK, Farber SA, Panettieri RA Jr, Peters SP, Penn RB. Regulation of phospholipase A2 by interleulin-1 in human airway smooth muscle.
Chest. 2003 Mar;123(3 Suppl):433S-4S. Review.

Tilley SL, Hartney JM, Erikson CJ, Jania C, Nguyen M, Stock J, McNeisch J, Valancius C, Panettieri RA Jr, Penn RB, Koller BH. Receptors and pathways mediating the effects of prostaglandin E2 on airway tone. Am J Physiol Lung Cell Mol Physiol. 2003 Apr;284(4):L599-606. Epub 2002 Dec 13.

Goncharova EA, Billington CK, Irani C, Vorotnikov AV, Tkachuk VA, Penn RB, Krymskaya VP, Panettieri RA Jr. Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration. Am J Respir Cell Mol Biol. 2003 Jul;29(1):19-27. Epub 2003 Jan 31.

Handley DA, Senanayake CH, Dutczak W, Benovic JL, Walle T, Penn RB, Wilkinson HS, Tanoury GJ, Andersson RG, Johansson F, Morley J. Biological actions of formoterol isomers. Pulm Pharmacol Ther. 2002;15(2):135-45.

Ammit AJ, Lazaar AL, Irani C, O'Neill GM, Gordon ND, Amrani Y, Penn RB, Panettieri RA Jr. Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth muscle cells: modulation by glucocorticoids and beta-agonists. Am J Respir Cell Mol Biol. 2002 Apr;26(4):465-74.

Billington CK, Penn RB. m3 muscarinic acetylcholine receptor regulation in the airway.
Am J Respir Cell Mol Biol. 2002 Mar;26(3):269-72. Review.

Pascual RM, Billington CK, Hall IP, Panettieri RA Jr, Fish JE, Peters SP, Penn RB. Mechanisms of cytokine effects on G protein-coupled receptor-mediated signaling in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2001 Dec;281(6):L1425-35.

Penn RB, Pascual RM, Kim YM, Mundell SJ, Krymskaya VP, Panettieri RA Jr, Benovic JL. Arrestin specificity for G protein-coupled receptors in human airway smooth muscle.
J Biol Chem. 2001 Aug 31;276(35):32648-56. Epub 2001 Jun 20.

Billington CK, Pascual RM, Hawkins ML, Penn RB, Hall IP. Related Articles, Links
Interleukin-1beta and rhinovirus sensitize adenylyl cyclase in human airway smooth-muscle cells. Am J Respir Cell Mol Biol. 2001 May;24(5):633-9.

Ammit AJ, Hastie AT, Edsall LC, Hoffman RK, Amrani Y, Krymskaya VP, Kane SA, Peters SP, Penn RB, Spiegel S, Panettieri RA Jr. Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J. 2001 May;15(7):1212-4.

Mundell SJ, Olah ME, Panettieri RA, Benovic JL, Penn RB. Regulation of G protein-coupled receptor-adenylyl cyclase responsiveness in human airway smooth muscle by exogenous and autocrine adenosine. Am J Respir Cell Mol Biol. 2001 Feb;24(2):155-63.

Penn RB, Pronin AN, Benovic JL. Regulation of G protein-coupled receptor kinases.
Trends Cardiovasc Med. 2000 Feb;10(2):81-9. Review.

Ammit AJ, Hoffman RK, Amrani Y, Lazaar AL, Hay DW, Torphy TJ, Penn RB, Panettieri RA Jr. Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate. Am J Respir Cell Mol Biol. 2000 Dec;23(6):794-802.

Krymskaya VP, Orsini MJ, Eszterhas AJ, Brodbeck KC, Benovic JL, Panettieri RA Jr, Penn RB. Mechanisms of proliferation synergy by receptor tyrosine kinase and G protein-coupled receptor activation in human airway smooth muscle. Am J Respir Cell Mol Biol. 2000 Oct;23(4):546-54.

Santini F, Penn RB, Gagnon AW, Benovic JL, Keen JH. Selective recruitment of arrestin-3 to clathrin coated pits upon stimulation of G protein-coupled receptors.
J Cell Sci. 2000 Jul;113 ( Pt 13):2463-70.

Ramos-Ruiz R, Penela P, Penn RB, Mayor F Jr. Analysis of the human G protein-coupled receptor kinase 2 (GRK2) gene promoter: regulation by signal transduction systems in aortic smooth muscle cells. Circulation. 2000 May 2;101(17):2083-9.

Eckhart AD, Duncan SJ, Penn RB, Benovic JL, Lefkowitz RJ, Koch WJ. Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Circ Res. 2000 Jan 7-21;86(1):43-50.

Billington CK, Hall IP, Mundell SJ, Parent JL, Panettieri RA Jr, Benovic JL, Penn RB. Inflammatory and contractile agents sensitize specific adenylyl cyclase isoforms in human airway smooth muscle. Am J Respir Cell Mol Biol. 1999 Nov;21(5):597-606.

Orsini MJ, Krymskaya VP, Eszterhas AJ, Benovic JL, Panettieri RA Jr, Penn RB. MAPK superfamily activation in human airway smooth muscle: mitogenesis requires prolonged p42/p44 activation. Am J Physiol. 1999 Sep;277(3 Pt 1):L479-88.

Krymskaya VP, Penn RB, Orsini MJ, Scott PH, Plevin RJ, Walker TR, Eszterhas AJ, Amrani Y, Chilvers ER, Panettieri RA Jr. Phosphatidylinositol 3-kinase mediates mitogen-induced human airway smooth muscle cell proliferation. Am J Physiol. 1999 Jul;277(1 Pt 1):L65-78.

Penn RB, Parent JL, Pronin AN, Panettieri RA Jr, Benovic JL. Pharmacological inhibition of protein kinases in intact cells: antagonism of beta adrenergic receptor ligand binding by H-89 reveals limitations of usefulness. J Pharmacol Exp Ther. 1999 Feb;288(2):428-37.

Penn RB, Panettieri RA Jr, Benovic JL. Mechanisms of acute desensitization of the beta2AR-adenylyl cyclase pathway in human airway smooth muscle. Am J Respir Cell Mol Biol. 1998 Aug;19(2):338-48.

Kallal L, Gagnon AW, Penn RB, Benovic JL. Visualization of agonist-induced sequestration and down-regulation of a green fluorescent protein-tagged beta2-adrenergic receptor. J Biol Chem. 1998 Jan 2;273(1):322-8.

Goodman OB Jr, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL. Role of arrestins in G-protein-coupled receptor endocytosis.
Adv Pharmacol. 1998;42:429-33.

Goodman OB Jr, Krupnick JG, Santini F, Gurevich VV, Penn RB, Gagnon AW, Keen JH, Benovic JL. Beta-arrestin acts as a clathrin adaptor in endocytosis of the beta2-adrenergic receptor. Nature. 1996 Oct 3;383(6599):447-50.

Penn RB, Shaver JR, Zangrilli JG, Pollice M, Fish JE, Peters SP, Benovic JL. Effects of inflammation and acute beta-agonist inhalation on beta 2-AR signaling in human airways.
Am J Physiol. 1996 Oct;271(4 Pt 1):L601-8.

Penn RB, Frielle T, McCullough JR, Aberg G, Benovic JL. Comparison of R-, S-, and RS-albuterol interaction with human beta 1- and beta 2-adrenergic receptors.
Clin Rev Allergy Immunol. 1996 Spring;14(1):37-45.

Penn RB, Kelsen SG, Benovic JL. Regulation of beta-agonist- and prostaglandin E2-mediated adenylyl cyclase activity in human airway epithelial cells.
Am J Respir Cell Mol Biol. 1994 Oct;11(4):496-505.

Penn RB, Benovic JL. Structure of the human gene encoding the beta-adrenergic receptor kinase. J Biol Chem. 1994 May 27;269(21):14924-30.

Penn RB, Wolfson MR, Shaffer TH. Developmental differences in tracheal cartilage mechanics. Pediatr Res. 1989 Nov;26(5):429-33.

Shaffer TH, Bhutani VK, Wolfson MR, Penn RB, Tran NN. In vivo mechanical properties of the developing airway. Pediatr Res. 1989 Feb;25(2):143-6.

Penn RB, Wolfson MR, Shaffer TH. Effect of tracheal smooth muscle tone on collapsibility of immature airways. J Appl Physiol. 1988 Aug;65(2):863-9.

Penn RB, Wolfson MR, Shaffer TH. Effect of ventilation on mechanical properties and pressure-flow relationships of immature airways. Pediatr Res. 1988 May;23(5):519-24.

Penn RB, Wolfson MR, Shaffer TH. Influence of smooth muscle tone and longitudinal tension on the collapsibility of immature airways. Pediatr Pulmonol. 1988;5(3):132-8.

Book Chapters

Penn, R. B., and J. L. Benovic. Regulation of G protein-coupled receptors. In Handbook of Physiology, Section 7: Endocrinology, Vol. 1: Cellular Endocrinology, Edited by Conn, PM., Oxford University Press, 1998: 125-164.

Goodman, O. B., J. G. Krupnick, F. Santini, V. V. Gurevich, R. B. Penn, A. Gagnon, J. H. Keen, and J. L. Benovic. Role of arrestins in G protein-coupled receptor endocytosis. in Catecholamines: Bridging Basic Science with Clinical Medicine. Advances in Pharmacology, vol 42. D. Goldstein, ed.