Center for Matrix Biology - Vanderbilt University and Medical Center

John S. Penn, Ph.D.
Professor in the Department of Ophthalmology and Visual Sciences

	Office Address:	2115 21st Ave. S., 8009 MCE
	Mailing Address:	2115 21st Ave. S., 8009 MCE Nashville, TN 37232-8808
	Lab address:	8009 MCE, North Tower
	Phone:	(615) 936-1485
	FAX:	(615) 936-1540
		email \| website

Secondary appointment in the Cell and Developmental Biology department.

Research Summary

My long-standing interest is in the molecular basis of ocular angiogenesis. The over-reaching goal of my research is to characterize the process of retinal angiogenesis, and to begin to develop preventive strategies based on understanding gained from in vitro and in vivo studies. During the past decade, we have continued to refine and characterize our experimental models, and we find them particularly well suited for investigations of the cellular and molecular aspects of angiogenesis in blinding diseases. We now propose to utilize these tools (e.g., retinal microvascular endothelial cells, Muller cells and astrocytes in culture, and rodent models of retinopathy of prematurity) to address two basic aims. The first aim is to investigate the mechanism by which non-steroidal anti-inflammatory drugs (NSAID) inhibit angiogenesis. The angiostatic activity of NSAID has long been recognized in several tumor types. However, their potency and the role of their target, cyclo-oxygenase, in ocular angiogenesis is largely undefined, although it is clear that important differences exist between the effects of NSAID on angiogenesis in tumors and in the retina.

The second aim is to investigate the angiostatic effect of penetrating ocular injury. Recently, we have discovered that dry needle penetration of the eye globe inhibits abnormal retinal and preretinal neovascularization. We call this phenomenon ?ocupuncture?. The pattern of the inhibitory influence implies that an antiangiogenic factor is released from the wound site and diffuses throughout the eye, exerting a stronger effect in the injured quadrant and a weaker effect in the opposite quadrant. Vitreous protein harvested from injured eyes shows potent angiostatic activity, both in VEGF-treated retinal microvascular endothelial cells and when administered to rats induced to display ROP-like pathology. This suggests that the ultimate answer to limiting retinal angiogenesis may lie within the retina's natural battery of inducible factors. We have begun the search for candidates using 2-D gel electrophoresis and gene microarray analysis to identify the responsible factors. We plan to characterize this phenomenon, using several genomics and proteomics methods to determine which one or more of these factors may play a role in the injury effect. Identification of endogenous retinal angiostatic factors will allow for the development of novel therapies for retinal neovascular pathologies. Therapeutic strategies that seek to regulate the synthesis and release of candidate endogenous factors provide distinct advantages over administration of exogenous agents.

Research Keywords

Pharmacology, Proteomics, Signal transduction, Stem cells, Vision,

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Associated initiative(s):

Angiogenesis

Biomaterials

Fibrosis

Tissue Regeneration

Tumor Microenvironment

Wound Repair

Career opportunities:
Postdoctoral Position Available

Selected Publications

» Penn, JS, Madan, A, Caldwell, RB, Bartoli, M, Caldwell, RW, Hartnett, ME Vascular endothelial growth factor in eye disease Prog Retin Eye Res 2008. 27:331-71

» Berkowitz, BA, Roberts, R, Penn, JS, Gradianu, M High-resolution manganese-enhanced MRI of experimental retinopathy of prematurity Invest Ophthalmol Vis Sci 2007. 48:4733-40

» Barnett, JM, McCollum, GW, Fowler, JA, Duan, JJ, Kay, JD, Liu, RQ, Bingaman, DP, Penn, JS Pharmacologic and genetic manipulation of MMP-2 and -9 affects retinal neovascularization in rodent models of OIR Invest Ophthalmol Vis Sci 2007. 48:907-15

» Kramerov A.A., Saghizadeh M., Pan H., Kabosova A., Montenarh M., Ahmed K., Penn J.S., Chan C.K., Hinton D.R., Grant M.B. and Ljubimov A.V. Expression of protein kinase CK2 in astroglial cells of normal and neovascularized retina Am J Pathol 2006. 168(5):1722-1736

» Lutty G.A., Chan-Ling T., Phelps D.L., Adamis A.P., Berns K.I., Chan C.K., Cole C.H., D?Amore P.A., Das, A., Deng W-T., Dobson V., Flynn J.T., Friedlander M., Fulton A., Good W.V., Grant, M.B., Hansen R., Hauswirth W.V., Hardy R.J., Hinton D.R., Hughes S., McLeod D.S., Palmer E.A., Patz A., Penn J.S., Raisler B.J., Repka M.X., Saint-Geniez M., Shaw L.C., Shima D.T., Smith B.T., Smith L.E.H., Tahija S.G., Tasman W., Trese M.T. Proceedings of the Third International Symposium on Retinopathy of Prematurity: An update on ROP from the lab to the nursery Molecular Vision 2006. 12:532-580

» Penn, JS, McCollum, GW, Barnett, JM, Werdich, XQ, Koepke, KA, Rajaratnam, VS Angiostatic effect of penetrating ocular injury: role of pigment epithelium-derived factor Invest Ophthalmol Vis Sci 2006. 47:405-14

» Werdich, XQ, Penn, JS Src, Fyn and Yes play differential roles in VEGF-mediated endothelial cell events Angiogenesis 2006. 8:315-26

» Chen, J., Hicks, D., Brantley-Sieders, D., Cheng, N., McCollum, G.W., Werdich, X.Q. and Penn, J.S. Inhibition of Retinal Neovascularization by Soluble EphA2 Receptor Exp. Eye Res 2006. 82(4):664-673

» Werdich, XQ, Penn, JS Specific involvement of SRC family kinase activation in the pathogenesis of retinal neovascularization Invest Ophthalmol Vis Sci 2006. 47:5047-56

» Anderson, R.E. and Penn, J.S. Environmental light and heredity provoke adaptive changes in retinal DHA levels that affect retinal function. Lipids 2004. 39(11): 1121-1124

» McCollum, GW, Rajaratnam, VS, Bullard, LE, Yang, R, Penn, JS Herbimycin A inhibits angiogenic activity in endothelial cells and reduces neovascularization in a rat model of retinopathy of prematurity Exp Eye Res 2004. 78:987-95

» York, JR, Landers, S, Kirby, RS, Arbogast, PG, Penn, JS Arterial oxygen fluctuation and retinopathy of prematurity in very-low-birth-weight infants J Perinatol 2004. 24:82-7

» Werdich, XQ, McCollum, GW, Rajaratnam, VS, Penn, JS Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy Exp Eye Res 2004. 79:623-30

» Bullard, Lawrence E, Qi, Xiang, Penn, John S Role for extracellular signal-responsive kinase-1 and -2 in retinal angiogenesis Invest Ophthalmol Vis Sci 2003. 44:1722-31

» Penn, JS, Rajaratnam, VS Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity Invest Ophthalmol Vis Sci 2003. 44:5423-9

» Penn, J S, Rajaratnam, V S, Collier, R J, Clark, A F The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity Invest Ophthalmol Vis Sci 2001. 42:283-90

» Penn, J S, Li, S, Naash, M I Ambient hypoxia reverses retinal vascular attenuation in a transgenic mouse model of autosomal dominant retinitis pigmentosa Invest Ophthalmol Vis Sci 2000. 41:4007-13

» Shafiee A, Roberts DD, Penn JS, Blake DA Thrombospondin (TSP) peptides inhibit angiogenesis in retinal explant assay and rat model of retinopathy of prematurity Invest 2000. 41:2378-2388

» Berkowitz, BA, Lukaszew, RA, Mullins, CM, Penn, JS Impaired hyaloidal circulation function and uncoordinated ocular growth patterns in experimental retinopathy of prematurity Invest Ophthalmol Vis Sci 1998. 39:391-6

» Berkowitz, BA, Roberto, KA, Penn, JS The vitreous protein concentration is increased prior to neovascularization in experimental ROP Curr Eye Res 1998. 17:218-21

» Robbins, S.G., Rajaratnam, V.S. and Penn, J.S Evidence for upregulation and redistribution of vascular endothelial growth factor receptors flt-1 and flk-1 in the oxygen-injured rat retina Growth Factors 1998. 16:1-9

» Berkowitz, B.A., R.A. Lukaszew, C.M. Mullins and J.S. Penn Impaired hyaloidal circulation function and uncoordinated ocular growth patterns in experimental retinopathy of prematurity Invest. Ophthalmol. Vis. Sci. 1998. 39:391-396

» Berkowitz, BA, Penn, JS Abnormal panretinal response pattern to carbogen inhalation in experimental retinopathy of prematurity Invest Ophthalmol Vis Sci 1998. 39:840-5

» Berkowitz, B.A. and J.S. Penn Abnormal panretinal response pattern to carbogen inhalation in experimental retinopathy of prematurity Invest. Ophthalmol. Vis. Sci. 1998. 39:838-843

» Berkowitz, B.A., K.A. Roberto and J.S. Penn The vitreous protein concentration is increased prior to neovascularization in experimental ROP Curr. Eye Res. 1998. 17:218-221

» Penn, J.S., Tolman, B.L. and L.E. Bullard Effect of a water soluble vitamin E analogue,Trolox, on retinal vascular development in an animal model of retinopathy of prematurity Free Rad. Biol. Med. 1997. 22:977-984

» Kommonen, B.W., U. Karhunen, T. Kylma, W.W. Dawson and J.S. Penn Impaired retinal function in young labrador retriever dogs heterozygous for late-onset rod-cone degeneration Vis. Res 1997. 37:365-370

» Niesman MR, Johnson KA, and Penn JS Therapeutic effect of liposomal superoxide dismutase in an animal model of retinopathy of prematurity Neurochem. Res 1997. 22:597-605

» Robbins, S.G., Conaway, J.R., Tolman, B.L., Roberto, K.A. and Penn, J.S Detection of vascular endothelial growth factor (VEGF) protein in vascular and non-vascular cells of the normal and oxygen-injured rat retina Growth Factors 1997. 14:279-295

» Penn, J.S. and M.M. Henry Assessing retinal neovascularization in an animal model of proliferative retinopathy Microvasc. Res 1996. 51:126-130

» Roberto, K.A., B.L. Tolman and J.S. Penn Long-term retinal vascular abnormalities in an animal model of retinopathy of prematurity Cur. Eye Res. 1996. 15:932-937

» Kommonen, B.W., T. Kylma, R.J. Cohen, J.S. Penn, L. Paulin, M.Y. Hurwitz and R.L. Hurwitz Early changes in cyclic GMP levels and ultrastructure in photoreceptor degeneration in Labrador Retrievers Ophthalmic Res 1996. 28:19-28

» Penn, J.S. and M.M. Henry Evaluation of blood vessel assessment techniques in animals with retinal vascular disease J. Ophthal. Phot 1996. 18:26-33

» Penn JS, Henry MM, Tolman BL and Wall PT The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats Invest. Ophthalmol. Vis. Sci. 1995. (10):2063-2070

» Kommonen, B.W., J.S.Penn, T. Kylma, U. Karhunen, W.W. Dawson, B.L. Tolman, and T. Ukkola Early morphometry of a retinal dystrophy in Labrador Retrievers Acta Ophthalmologica 1994. 72:203-210

» Penn, J.S., B.L. Tolman, and M.M. Henry Oxygen-induced retinopathy in the rat: relationship of retinal non-perfusion to subsequent neovascularization 35Invest. Ophthalmol. Vis. Sci 1994. (9):3429-3435

» Penn, J.S., M.M. Henry and B.L. Tolman Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat Pediatr. Res. 1994. 36:724-731

» Penn, J.S., B.L. Tolman and L.A. Lowery Variable oxygen exposure causes pre-retinal neovascularization in the newborn rat Invest. Ophthalmol. Vis. Sci 1993. 34:576-585

» Penn, J.S. and B.D. Johnson Fluorescein angiography as a means of assessing retinal vascular pathology in oxygen-exposed newborn rats Curr. Eye Res 1993. 12:561-570

» Penn, J.S., B.L. Tolman, C.A. Koutz and L.A. Lowery Oxygen-induced retinopathy in the rat: Hemorrhages and dysplasias may lead to retinal detachments Cur. Eye Res. 1992. 11:939-953

» Penn, J.S. and C.A. Gay A new method of vascular analysis for animal models of retinopathy of prematurity Exp. Eye Res. 1992. 54:329-336

» Penn, J.S., L.A. Thum and M.I. Naash Oxygen-induced retinopathy in the rat: Vitamins C and E as potential therapies Invest. Ophthalmol. Vis. Sci 1992. 33:1836-1845

» Penn, J.S., B.L. Tolman, L.A. Thum and C.A. Koutz Effect of light history on the rat retina: Timecourse of morphological adaptation and readaptation Neurochem. Res. 1991. 17:91-99

» Larrazabal, L.I. and J.S. Penn Fluorescein angiography in the newborn rat: Implications in oxygen-induced retinopathy Invest. Ophthalmol. Vis. Sci 1990. 31:810-818

» Penn, J.S Oxygen-induced retinopathy in the rat: Possible contribution of peroxidation reactions Doc. Ophthalmol. 1990. 74:179-186

» Williams, T.P., J.S. Penn, R.A. Bush, and C.L. Makino Renewal of rod outer segments and regulation of daily photon catch by the rat retina Pro. Yamada Conf. 1989. :255-260

» Penn, J.S. and L.A. Thum Oxygen-induced retinopathy in the rat: Role of vitamin E in defending against peroxidation Ann. N.Y. Acad. Sci 1989. :495-497

» Larrazabal, L.I. and J.S. Penn Study of ocular vasculature in the newborn rat by fluorescein angiography J. Ophthal. Phot. 1989. 11:49-52

» Penn, J.S., L.A. Thum and M.I. Naash Photoreceptor physiology in the rat is governed by the light environment Exp. Eye Res 1989. 49:205-215

» Penn, J.S., L.A. Thum, M. Rhem, and S.J. Dell Effects of oxygen-rearing on the electroretinogram and GFA-protein in the rat Invest. Ophthalmol. Vis. Sci. 1988. 29:1623-1630