Sears Lab staff, left to right: George Hoppe, PhD, and Jonathan Sears, MD
Director: Jonathan Sears, MD
Department of Ophthalmic Research
Cole Eye Institute
9500 Euclid Avenue, i32
Office telephone: 216.444.8157
Our lab is interested in the regulation of retinal vascular permeability and angiogenesis in the severely premature infant. We have undertaken two approaches to understanding the basic biology of retinopathy of prematurity (ROP). First we are investigating the possibility of creating normal vascularization in the setting of hyperoxia (phase I of ROP), a process which usually causes vaso-obliteration and subsequent ischemia that leads to hypoxia of retinal tissues (phase II of ROP) and neovascularization. Our hypothesis is that replacing growth factors present in normal retinal development but absent during hyperoxia can enable physiologic and sequential development of the retina despite the hyperoxic environment of the severely premature infant. We propose to activate the transcription factor(s) responsible for the induction of these key gene products, focusing on hypoxia inducible factors (HIF) 1 and 2.
Second, we have recently demonstrated that an important corticosteroid, triamcinolone acetonide, decreases the secretion of vascular endothelial growth factor (VEGF) by destabilizing VEGF mRNA through the non-genomic steroid receptor. We hypothesize that this receptor is membrane bound and are currently isolating and characterizing it as a target for therapies that modulate vascular permeability and proliferation without the side effects attributed to the classical, cytosolic ligand dependent steroid receptor.
Finally, we have a continued interest in the post-translation, reversible redox modification of proteins by thiol/disulfide exchange, termed protein S-glutathionylation (PSSG). We have demonstrated that heat shock protein 70 (Hsp70) and high mobility group protein B1 (HMGB1) are substrates of the enzyme that facilitates glutathionylation. In the case of Hsp70, PSSG increases its chaperone activity. The function of HMGB1 is largely unknown, but Dr. Hoppe has recently identified key thiol residues that target HMGB1 to the nucleus and has reported its circadian based localization within the outer retina.
- Beck W.F., Sears JE., Brudvig G.W., Kulawiec R.J. and Crabtree R.H.: Oxidation of exogenous substrates by the 02 evolving center of Photosystem II and related catalytic air oxidation of secondary alcohols via a tetra nuclear manganese (IV) complex. Tetrahedron 45:4903 4911, 1989.
- Ricker KW, Sears JE, Beck WF, Brudvig GW. Mechanism of irreversible inhibition of 02 evolution in photosystem II by Tris (hydroxymethyl) aminoethane. Biochemistry 1991 30: 7888-94.
- Sears JE., Fikrig E., Nakagawa T.N, Marcantonio N., Deponte K., Kantor F. and Flavell R.A.: Molecular mapping of Osp A mediated immunity against Borrelia burgdorferi, the agent of Lyme disease. Journal of Immunology 147:1995 2000, 1991.
- Nakagawa T.Y., von Grafenstein H., Sears JE, Williams J., Janeway C.A. and Flavell R.A.: The use of the polymerase chain reaction to map CD4 + T cell epitopes. European Journal of Immunology 21:2851 2855, 1991.
- Sears JE, Fikrig E, Nakagawa TY, Deponte K, Marcantonio N, Kantor FS, Flavell RA. Molecular mapping of Osp-A mediated immunity against Borrelia burgdorferi, the agent of Lyme disease. J Immunol. 1991 Sep 15;147(6):1995-2000.
- Fikrig E., Barthold S.W., Sears JE., Telford S., Speilman A., Kantor F.S. and Flavell, R.A.: A recombinant vaccine for Lyme disease. Lyme Disease: Molecular and Immunologic Approaches, Cold Spring Harbor Press 37:716 28, 1992.
- Mead A., Sears JE. and Sears, M.L.: Transepithelial transport of ascorbic acid by the isolated intact ciliary epithelial bilayer of the rabbit eye. Journal of Ocular Pharmacology and Therapeutics 12(3): 253-8, 1996.
- Wan, X., Sears JE., Chen, S. and Sears, M. Circadian aqueous flow mediated by -arrestin induced homologous desensitization. Experimental Eye Research 64:1005, 1997.
- Sears, JE, Nakano, T. and Sears, M. Adrenergic mediated Connexin43 phosphorylation in the ocular ciliary epithelium. Current Eye Research 17: 104-107, 1998.
- Sears J, Nakano T, Sears M. Adrenergic-mediated connexin43 phosphorylation in the ocular ciliary epithelium. Curr Eye Res. 1998 Jan;17(1):104-7.
- Chai YC, Hoppe, G, Sears, JE. Reversal of protein S-glutathiolation by glutaredoxin in the retinal pigment epithelium. Exp Eye Res 2003; 76(2): 155-159.
- Hoppe, G, Chai YC, Sears, JE. Endogenous Oxidoreductase Expression is Induced by Aminoglycosides. Archives of Biochemistry and Biophysics 2003 414 19-23.
- Hoppe, G, Chai YC, Crabb, JW, Sears, JE. Protein S-glutathionylation in the retinal pigment epithelium converts heat shock protein 70 to an active chaperone. Exp Eye Res 2004, 78: 1085-92.
- Hoppe G, O'Neil J, Hoff HF, and Sears JE. Products of Lipid Peroxidation Induce Missorting of the Principal Lysosomal Proteasein the retinal pigment epithelium. Biochemica Biophysica Acta 2004, 1689: 33-41
- Hoppe G, O'Neil J, Hoff HF, and Sears JE. Accumulation of Oxidized Lipid-Protein Complexes alters phagosome maturation in the retinal pigment epithelium Cell Mol Life Sci 2004, 61: 1664-74.
- Hoppe G, Chai YC, Crabb JW, Sears J. Protein s-glutathionylation in retinal pigment epithelium converts heat shock protein 70 to an active chaperone. Exp Eye Res. 2004 Jun;78(6):1085-92.
- Sears JE, and Hoppe G. Triamcinolone Acetonide Destabilizes VEGF mRNA in Müller Cells under Continuous Cobalt Stimulation Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4336-41
- Hoppe G, Talcott KE, Bhattacharya SK, Crabb JW, Sears JE.Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006 Aug 2.
- Yokoyama T, Yamane K, Minamoto A, Tsukamoto H, Yamashita H, Izumi S, Hoppe G, Sears JE, Mishima HK.High glucose concentration induces elevated expression of anti-oxidant and proteolytic enzymes in cultured human retinal pigment epithelial cells. Exp Eye Res. 2006 Sep;83(3):602-9.
- Ebrahem Q, Renganathan K, Sears J, Vasanji A, Gu X, Lu L, Salomon RG, Crabb JW, Anand-Apte B.Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration. Proc Natl Acad Sci U S A. 2006 Sep 5;103(36):13480-4. Epub 2006 Aug 25.
- Hoppe G, Talcott KE, Bhattacharya SK, Crabb JW, Sears JE.Molecular basis for the redox control of nuclear transport of the structural chromatin protein Hmgb1. Exp Cell Res. 2006 Nov 1;312(18):3526-38. Epub 2006 Aug 2.
- Ebrahem Q, Minamoto A, Hoppe G, Anand-Apte B, Sears JE Triamcinolone acetonide inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors. Invest Ophthalmol Vis Sci. 2006 Nov;47(11):4935-41.
- Sears, JE, Gilman, J., and Sternberg, P., Jr. Familial retinal arterial tortuosity with retinal hemorrhages. Arch Ophthalmol. 1998; 116:1185-1188
- Sears, JE., Capone, S., Aaberg, T.M., Sr. and January, B. Ciliary body endophotocoagulation during pars plana vitrectomy in pediatric patients, American Journal of Ophthalmology 1998 126: 723-725.
- Sears JE., Capone A. Jr., Aaberg, T.M. Sr., Lewis H., Grossniklaus H., Sternberg P, Jr., DeJuan E. Surgical Management of foveal neovascularization in children. Ophthalmology. 106 (5) 920-924, 1999.
- Sears J, Capone A Jr, Aaberg T Sr, Lewis H, Grossniklaus H, Sternberg P Jr, DeJuan E. Surgical management of subfoveal neovascularization in children. Ophthalmology. 1999 May;106(5):920-4.
- Kaiser, P.K., Reimann, C.D., Sears, J.E., and Lewis, H. Macular Traction Detachment and Diabetic Macular Edema Associated with Posterior Hyaloidal Traction. Am J Ophthalmol 2001; 131:44-49.
- Sears, JE, Aaberg, T.M., Sr., Daiger, S.P., Moshfeghi, D. Splice Site Mutation in the Peripherin/RDS Gene-Associated With Pattern Dystrophy of the Retina. Am J Ophthalmol, 2001;132: 693-697.
- Sullivan, P., Philsecker, L., and Sears, JE. Limited Macular Translocation with Scleral Retraction Sutures. British Journal of Ophthalmology, 2002, 86; 434-439.
- Moshfeghi, DM, Kaiser, PK, Grossniklaus, HE, Sternberg, P., Jr., Sears, JE, Johnson, MW, Ratliff, N, Branco, A, Blumenkranz, MS, Lewis H. Clinicopathologic study after submacular removal of choroid neovascular membranes treated with verteporfin ocular photodynamic therapy. Am J Ophthalmol 2003 135: 343-350.
- Moshfeghi D, Laier PK, Scott IU, Sears JE et al. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol 2003, 136:791-6.
- Cahill MT, Kaiser PK, Sears JE, Fekrat S. The effect of arteriovenous sheathotomy on cystoid macular oedema secondary to branch retinal vein occlusion. Br J Ophthalmol. 2003 Nov;87(11):1329-32.
- Al-Khayer K, Hagstrom S, Pauer G, Zegarra H, Sears JE, Traboulsi EI. 30 year follow up of a patient with leber congenital amaurosis and novel RPE65 mutations. Am J Ophthalmol. 2004, 137:375-7.
- Cahill MT, Kaiser PK, Sears JE, Fekrat S. The effect of arteriovenous sheathotomy on cystoid macular edema secondary to branch retinal vein occlusion. Br J Ophthalmol 2003 87: 1329-32.
- Moshfeghi D, Sears JE, Lewis H. Submacular surgery for choroidal neovascularization following nocardial endophthalmitis. Retina 2004 24:161-4.
- Roth D, Sears JE, Lewis H. Removal of retained subfoveal perfluoro-n-octane liquid. Am J Ophthalmol 2004 138: 287-89.
- Singh AD, Kaiser PK, Sears JE, et al. Photodynamic therapy of circumscribed choroidal hemangiomas. Br J Ophthalmol 2004 88: 1414-18.
- Moshfeghi D, Kim BY, Kaiser PK, Sears JE, Smith SD. Appositional suprachoroidal hemorrhage: a case control study. Am J Ophthalmols 2004 138: 959-63.
- Al-Khayer K, Hagstrom S, Pauer G, Zegarra H, Sears J, Traboulsi EI. Thirty-year follow-up of a patient with leber congenital amaurosis and novel RPE65 mutations. Am J Ophthalmol. 2004 Feb;137(2):375-7.
- Moshfeghi D, Kaiser P, Bakri SJ, Kaiser RS, Maturi RK, Sears JE. Presumed sterile endophthalmitis following intravitreal triamcinolone acetonide. Ophthal Surg Lasers Imaging 2005 36: 24-29.
- Singh AD Kaiser PK, Sears JE. Choroidal hemangioma Ophthalmol Clin North Am 2005 18:151-161.
- Bakri SJ, Sears JE, Singh AD. Transient closure of a retinal capillary hemangioma with verteporfin photodynamic therapy. Retina. 2005 Dec;25(8):1103-4.
- Singh RP, Patel C, Sears JE. Management of subretinal macular haemorrhage by direct administration of tissue plasminogen activator. Br J Ophthalmol. 2006 Apr;90(4):429-31.
- Saavedra E, Singh AD, Sears JE, Ratliff NB. Plexiform pigmented schwannoma of the uvea. Surv Ophthalmol. 2006 Mar-Apr;51(2):162-8.
- Taban M, Kosmorsky GS, Singh AD, Sears JE.Choroidal folds secondary to parasellar meningioma. Eye. 2006 Jun 16.
- Ou JI, Moshfeghi DM, Tawansy K, Sears JE. Macular hole in the shaken baby syndrome. Arch Ophthalmol. 2006 Jun;124(6):913-5.
- Singh RP, Sears JE. Retinal pigment epithelial tears after pegaptanib injection for exudative age-related macular degeneration. Am J Ophthalmol. 2006 Jul;142(1):160-2.
- Bakri SJ, Sears JE, Lewis H.Management of macular hole and submacular hemorrhage in the same eye. Graefes Arch Clin Exp Ophthalmol. 2006 Jul 27; [Epub ahead of print] PMID: 16871381.
- Taban M, Ufret-Vincenty RL, Sears JE.Endophthalmitis after 25-gauge transconjunctival sutureless vitrectomy. Retina. 2006 Sep;26(7):830-1.
- Taban M, Sears JE, Singh AD.Ciliary body naevus. Eye. 2006 Oct 13; [Epub ahead of print].
- Brasil OF, Smith SD, Galor A, Lowder CY, Sears JE, Kaiser PK. Predictive factors for short term visual outcome after intravitreal triamcinolone acetonide injection for diabetic macular edema: an OCT study.Br J Ophthalmol. 2006 Nov 15; [Epub ahead of print]