Jonathan Sears, MD

Associate Professor of Ophthalmology, Cole Eye Institute

Research: “Prevention of Retinopathy of Prematurity”

Research

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.

Publications

Publications on PubMed

Ebrahem Q, Qi JH, Sugimoto M, Ali M, Sears JE, Cutler A, Khokha R, Vasanji A, Anand-Apte B. Increased neovascularization in mice lacking tissue inhibitor of metalloproteinases-3. Invest Ophthalmol Vis Sci. 2011 Aug 3;52(9):6117-23. Print 2011 Aug. PubMed PMID: 21282576; PubMed Central PMCID: PMC3175998.

Nicholson B, Ahmad B, Sears JE. Congenital optic nerve malformations. Int Ophthalmol Clin. 2011 Winter;51(1):49-76. Review. PubMed PMID: 21139477.

Sears NC, Sears JE. Oxygen and retinopathy of prematurity. Int Ophthalmol Clin. 2011 Winter;51(1):17-31. Review. PubMed PMID: 21139475.

Sachdeva R, Sears JE, Rychwalski PJ. A novel case of bilateral high myopia, cataract, and total retinal detachment associated with interstitial 11q deletion. Ophthalmic Genet. 2010 Jun;31(2):84-8. PubMed PMID: 20450311.

Sears JE. Stimulating angiogenesis to prevent ischemic retinopathy. Ophthalmology. 2009 Sep;116(9):1597-8. PubMed PMID: 19729095.

Barakat MR, Traboulsi EI, Sears JE. Coats’ disease, megalopapilla and Cornelia de Lange syndrome. Ophthalmic Genet. 2009 Jun;30(2):106-8. PubMed PMID: 19373684.

Vickerman MB, Keith PA, McKay TL, Gedeon DJ, Watanabe M, Montano M, Karunamuni G, Kaiser PK, Sears JE, Ebrahem Q, Ribita D, Hylton AG, Parsons-Wingerter P. VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks. Anat Rec (Hoboken). 2009 Mar;292(3):320-32. PubMed PMID: 19248164; PubMed Central PMCID: PMC2880175.

Sears JE, Pietz J, Sonnie C, Dolcini D, Hoppe G. A change in oxygen supplementation can decrease the incidence of retinopathy of prematurity. Ophthalmology. 2009 Mar;116(3):513-8. Epub 2009 Jan 20. PubMed PMID: 19157560.

Sears JE, Hoppe G, Ebrahem Q, Anand-Apte B. Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy. Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19898-903. Epub 2008 Dec 4. PubMed PMID: 19057008; PubMed Central PMCID: PMC2604934.

Sears JE. Anti-vascular endothelial growth factor and retinopathy of prematurity. Br J Ophthalmol. 2008 Nov;92(11):1437-8. PubMed PMID: 18952651.

Sears JE, Sonnie C. Anatomic success of lens-sparing vitrectomy with and without scleral buckle for stage 4 retinopathy of prematurity. Am J Ophthalmol. 2007 May;143(5):810-3. Epub 2007 Feb 28. PubMed PMID: 17335766.

Taban M, Sears JE, Crouch E, Schachat AP, Traboulsi EI. Acute idiopathic frosted branch angiitis. J AAPOS. 2007 Jun;11(3):286-7. Epub 2007 Jan 25. PubMed PMID: 17257872.

Hoppe G, Rayborn ME, Sears JE. Diurnal rhythm of the chromatin protein Hmgb1 in rat photoreceptors is under circadian regulation. J Comp Neurol. 2007 Mar 10;501(2):219-30. PubMed PMID: 17226794.

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. PubMed PMID: 17065510.

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. PubMed PMID: 16962095.

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. Epub 2006 May 11. PubMed PMID: 16697369.

Sears JE, Hoppe G. Triamcinolone acetonide destabilizes VEGF mRNA in Müller cells under continuous cobalt stimulation. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4336-41. PubMed PMID: 16249516.

Sears JE, Aaberg TA Sr, Daiger SP, Moshfeghi DM. Splice site mutation in the peripherin/RDS gene associated with pattern dystrophy of the retina. Am J Ophthalmol. 2001 Nov;132(5):693-9. PubMed PMID: 11704030.

Nakagawa TY, Von Grafenstein H, Sears JE, Williams J, Janeway CA, Flavell RA. The use of the polymerase chain reaction to map CD4+ T cell epitopes. Eur J Immunol. 1991 Nov;21(11):2851-5. PubMed PMID: 1718762.

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. PubMed PMID: 1716290. 1: Traboulsi EI, Ellison J, Sears J, Maumenee IH, Avallone J, Mohney BG. Aniridia with preserved visual function: a report of four cases with no mutations in PAX6. Am J Ophthalmol. 2008 Apr;145(4):760-4. Epub 2008 Feb 19. PubMed PMID: 18243151.

Renganathan K, Ebrahem Q, Vasanji A, Gu X, Lu L, Sears J, Salomon RG, Anand-Apte B, Crabb JW. Carboxyethylpyrrole adducts, age-related macular degeneration and neovascularization. Adv Exp Med Biol. 2008;613:261-7. Review. PubMed PMID: 18188953.

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. Erratum in: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15722. PubMed PMID: 16938854; PubMed Central PMCID: PMC1569188.

Hoppe G, O’Neil J, Hoff HF, Sears J. Accumulation of oxidized lipid-protein complexes alters phagosome maturation in retinal pigment epithelium. Cell Mol Life Sci. 2004 Jul;61(13):1664-74. PubMed PMID: 15224189.

Hoppe G, O’Neil J, Hoff HF, Sears J. Products of lipid peroxidation induce missorting of the principal lysosomal protease in retinal pigment epithelium. Biochim Biophys Acta. 2004 May 24;1689(1):33-41. PubMed PMID: 15158911.

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. PubMed PMID: 15109915.

Nakagawa TY, Von Grafenstein H, Sears JE, Williams J, Janeway CA, Flavell RA. The use of the polymerase chain reaction to map CD4+ T cell epitopes. Eur J Immunol. 1991 Nov;21(11):2851-5. PubMed PMID: 1718762.

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. PubMed PMID: 1716290.

Rickert KW, Sears J, Beck WF, Brudvig GW. Mechanism of irreversible inhibition of O2 evolution in photosystem II by Tris(hydroxymethyl)aminomethane. Biochemistry. 1991 Aug 13;30(32):7888-94. PubMed PMID: 1651110.

Sears J, Gilman J, Sternberg P Jr. Inherited retinal arteriolar tortuosity with retinal hemorrhages. Arch Ophthalmol. 1998 Sep;116(9):1185-8. PubMed PMID: 9747676.

Sears J, Nakano T, Sears M. Adrenergic-mediated connexin43 phosphorylation in the ocular ciliary epithelium. Curr Eye Res. 1998 Jan;17(1):104-7. PubMed PMID: 9472478.

Wan XL, Sears J, Chen S, Sears M. Circadian aqueous flow mediated by beta-arrestin induced homologous desensitization. Exp Eye Res. 1997 Jun;64(6):1005-11. PubMed PMID: 9301482.

Mead A, Sears J, Sears M. Transepithelial transport of ascorbic acid by the isolated intact ciliary epithelial bilayer of the rabbit eye. J Ocul Pharmacol

Ther. 1996 Fall;12(3):253-8. PubMed PMID: 8875331.

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. PubMed PMID: 10328390.