{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:28:58Z","timestamp":1786364938607,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United States\u2019 National Institutes of Health","award":["EY026662"],"award-info":[{"award-number":["EY026662"]}]},{"name":"United States\u2019 National Institutes of Health","award":["EY027005"],"award-info":[{"award-number":["EY027005"]}]},{"DOI":"10.13039\/100000928","name":"The Welch Foundation","doi-asserted-by":"publisher","award":["BK-0031"],"award-info":[{"award-number":["BK-0031"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]},{"award":["BK-0031"],"award-info":[{"award-number":["BK-0031"]}],"id":[{"id":"https:\/\/ror.org\/00np6vq88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Mass spectrometry-based retina proteomics is an emerging method applied to a better understanding of glaucomatous neurodegeneration. This study reports the identification of retinal proteins and processes associated with elevated intraocular pressure using the magnetic microbead model of glaucoma in mice with consideration of sex as a biological variable. The harvested retinas were analyzed by shotgun proteomics via nanoflow liquid chromatography\u2013electrospray ionization tandem mass spectrometry and label-free quantifications. Ingenuity Pathway Analysis\u00ae was used for biological interpretation of the resulting dataset. Sex had a statistically significant influence on elevated intraocular pressure-induced changes of retinal protein expressions, and principal component analysis of all identified, verified, and quantified proteins indicated a clear separation of the ocular hypertensive versus normotensive clusters in males, while this separation was far less pronounced in females. Metabolic functions were among the most predominant biological features affected by the increased intraocular pressure. While our results overlapped with many previous findings regarding disease pathology, they have also revealed previously unreported proteins, as well as molecular and physiological functions potentially implicated in glaucomatous neurodegeneration of the retina in a sex-dependent manner.<\/jats:p>","DOI":"10.3390\/ijms27167153","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:09Z","timestamp":1786361889000},"page":"7153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex-Dependent Responses in the Retina Proteome to Ocular Hypertension in a Mouse Model of Glaucoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4876-765X","authenticated-orcid":false,"given":"Khadiza","family":"Zaman","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Neuroscience, College of Biomedical and Translational Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Autumn B.","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5595-1346","authenticated-orcid":false,"given":"Katalin","family":"Prokai-Tatrai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, College of Biomedical and Translational Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8522-4112","authenticated-orcid":false,"given":"Denise M.","family":"Inman","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4559-3458","authenticated-orcid":false,"given":"Laszlo","family":"Prokai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, College of Biomedical and Translational Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The pathophysiology and treatment of glaucoma: A review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: A systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_3","first-page":"066","article-title":"Animal models of optic nerve diseases","volume":"18","year":"2004","journal-title":"Eye"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrneurol.2012.227","article-title":"The retina as a window to the brain\u2014From eye research to CNS disorders","volume":"9","author":"London","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Cehofski, L.J., Honor\u00e9, B., and Vorum, H. (2017). A review: Proteomics in retinal artery occlusion, retinal vein occlusion, diabetic retinopathy and acquired macular disorders. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18050907"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1002\/mas.21786","article-title":"Mass spectrometry-based retina proteomics","volume":"42","author":"Prokai","year":"2023","journal-title":"Mass Spectrom. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1007\/s10384-007-0507-5","article-title":"Proteomic analysis of rat retina in a steroid-induced ocular hypertension model: Potential vulnerability to oxidative stress","volume":"52","author":"Miyara","year":"2008","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4962","DOI":"10.1002\/pmic.200800978","article-title":"Proteomic study of DBA\/2J mice retina: Down-regulation of integrin \u03b27 correlated with retinal ganglion cell death","volume":"9","author":"Kanamoto","year":"2009","journal-title":"Proteomics"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Schallenberg, M., Prokosch, V., and Thanos, S. (2012). Regulation of retinal proteome by topical antiglaucomatous eye drops in an inherited glaucoma rat model. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033593"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Prokosch, V., Schallenberg, M., and Thanos, S. (2013). Crystallins are regulated biomarkers for monitoring topical therapy of glaucomatous optic neuropathy. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0049730"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4931","DOI":"10.1002\/jcb.29822","article-title":"Retinal proteomics of experimental glaucoma model reveal intraocular pressure-induced mediators of neurodegenerative changes","volume":"121","author":"Mirzaei","year":"2020","journal-title":"J. Cell Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zaman, K., Nguyen, V., Prokai-Tatrai, K., and Prokai, L. (2023). Proteomics-based identification of retinal protein networks impacted by elevated intraocular pressure in the hypertonic saline injection model of experimental glaucoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612592"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Reinehr, S., Guntermann, A., Theile, J., Benning, L., Grotegut, P., Kuehn, S., Serschnitzki, B., Dick, H.B., Marcus, K., and Joachim, S.C. (2022). Proteomic analysis of retinal tissue in an S100B autoimmune glaucoma model. Biology, 11.","DOI":"10.3390\/biology11010016"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00417-017-3678-x","article-title":"Proteomic profiling reveals crucial retinal protein alterations in the early phase of an experimental glaucoma model","volume":"255","author":"Anders","year":"2017","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Tonner, H., Hunn, S., Auler, N., Schmelter, C., Beutgen, V.M., von Pein, H.D., Pfeiffer, N., and Grus, F.H. (2022). A monoclonal anti-HMGB1 antibody attenuates neurodegeneration in an experimental animal model of glaucoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084107"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1001\/archopht.122.3.374","article-title":"Does sex matters in glaucoma?","volume":"122","author":"Higginbotham","year":"2004","journal-title":"Arch. Ophthalmol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1097\/ICU.0b013e3283360b7e","article-title":"Gender and glaucoma: What we know and what we need to know","volume":"21","author":"Vajaranant","year":"2010","journal-title":"Curr. Opin. Ophthalmol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1167\/iovs.62.13.9","article-title":"Influence of sex on neuroretinal degeneration: Six-month follow-up in rats with chronic glaucoma","volume":"62","author":"Rodrigo","year":"2021","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s13293-024-00645-9","article-title":"Quantitative proteomic profiling reveals sexual dimorphism in the retina and RPE of C57BL6 mice","volume":"15","author":"Jang","year":"2024","journal-title":"Biol. Sex Differ."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1167\/iovs.09-3921","article-title":"A novel method for the induction of experimental glaucoma using magnetic microspheres","volume":"52","author":"Samsel","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8609","DOI":"10.1523\/JNEUROSCI.2532-06.2006","article-title":"Early postnatal astroglial cells produce multilineage precursors and neural stem cells in vivo","volume":"26","author":"Ganat","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1093\/ilar\/ilu036","article-title":"Evidence should trump intuition by preferring inbred strains to outbred stocks in preclinical research","volume":"55","author":"Festing","year":"2014","journal-title":"ILAR J."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Grimm, H., Biller-Andorno, N., Buch, T., Dahlhoff, M., Davies, G., Cederroth, C.R., Maissen, O., Lukas, W., Passini, E., and T\u00f6rnqvist, E. (2023). Advancing the 3Rs: Innovation, implementation, ethics and society. Front. Vet. Sci., 10.","DOI":"10.3389\/fvets.2023.1185706"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"545","DOI":"10.2174\/092986730607220401122519","article-title":"IMP dehydrogenase: Mechanism of action and inhibition","volume":"6","author":"Hedstrom","year":"1999","journal-title":"Curr. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/hmg\/ddh061","article-title":"On the molecular pathology of neurodegeneration in IMPDH1-based retinitis pigmentosa","volume":"13","author":"Aherne","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1006\/exer.2000.0974","article-title":"Retinal degeneration following failed photoreceptor maturation in 5A11\/basigin null mice","volume":"72","author":"Ochrietor","year":"2001","journal-title":"Exp. Eye Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.bbrc.2022.11.074","article-title":"Reduced expression of basigin gene products in response to chronic inflammation may contribute to vision loss","volume":"638","author":"Gonzalez","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5122","DOI":"10.1523\/JNEUROSCI.3652-17.2018","article-title":"Structural and functional rescue of chronic metabolically stressed optic nerves through respiration","volume":"38","author":"Pappenhagen","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1007\/s00417-023-06099-w","article-title":"Park7 protects retinal ganglion cells and promotes functional preservation after optic nerve crush via regulation of the Nrf2 signaling pathway","volume":"261","author":"Ouyang","year":"2023","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107830","DOI":"10.1016\/j.exer.2019.107830","article-title":"DJ-1\/PARK7 inhibits high glucose-induced oxidative stress to prevent retinal pericyte apoptosis via the PI3K\/AKT\/mTOR signaling pathway","volume":"189","author":"Zeng","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Zaman, K., Kapic, A., Nguyen, V., and Prokai-Tatrai, K. (2026). Impact of orchiectomy on oxidative stress-induced neurodegeneration in the male rat retina: A proteomic analysis. Antioxidants, 15.","DOI":"10.3390\/antiox15040479"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Namme, J.N., Bepari, A.K., and Takebayashi, H. (2021). Cofilin signaling in the CNS Physiology and neurodegeneration. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910727"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, X., He, D., Yang, J., Li, B., Jiang, H., Liu, J., Xu, X., Shi, Z., Ni, N., and Mei, Y. (2023). Single-Cell Combined Transcriptional Sequencing to Explore Key Genes and Regulatory Mechanisms in Diabetic Retinopathy. Res. Sq.","DOI":"10.21203\/rs.3.rs-3174202\/v1"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lux, U.T., Meyer, J., Jahn, O., Davison, A., Babai, N., Gie\u00dfl, A., Wartenberg, A., Sticht, H., Brose, N., and Reim, K. (2024). Light-dependent regulation of neurotransmitter release from rod photoreceptor ribbon synapses involves an interplay of Complexin 4 and Transducin with the SNARE complex. Front. Mol. Neurosci., 17.","DOI":"10.3389\/fnmol.2024.1308466"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Youale, J., Bigot, K., Kodati, B., Jaworski, T., Fan, Y., Nsiah, N.Y., Pappenhagen, N., Inman, D.M., Behar-Cohen, F., and Bordet, T. (2022). Neuroprotective effects of transferrin in experimental glaucoma models. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232112753"},{"key":"ref_36","first-page":"101355","article-title":"Ferroptosis and retinal ganglion cell death in glaucoma: Mechanisms and therapeutic approaches","volume":"121","author":"Qin","year":"2025","journal-title":"J. Pharm. Anal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1113\/JP275779","article-title":"Role of recoverin in rod photoreceptor light adaptation","volume":"596","author":"Morshedian","year":"2018","journal-title":"J. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17705","DOI":"10.1038\/s41598-021-97162-1","article-title":"HSPA9\/Mortalin mediates axo-protection and modulates mitochondrial dynamics in neurons","volume":"11","author":"Thouard","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5497","DOI":"10.1111\/jcmm.14433","article-title":"Loss of retinal ganglion cells in a new genetic mouse model for primary open-angle glaucoma","volume":"23","author":"Reinehr","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Prokai-Tatrai, K., Zaman, K., Kapic, A., Hogan, K., Sanchez-Rodriguez, G., Silverio, A.E., Nguyen, V., Prokai, L., and Feola, A.J. (2025). Retina-targeted 17\u03b2-estradiol by the DHED prodrug rescues visual function and actuates neuroprotective protein networks after optic nerve crush in a rat model of surgical menopause. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26051846"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.celrep.2015.01.005","article-title":"Protein-4.1G-Mediated Membrane Trafficking Is Essential for Correct Rod Synaptic Location in the Retina and for Normal Visual Function","volume":"10","author":"Sanuki","year":"2015","journal-title":"Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Soundararajan, A., Wang, T., and Pattabiraman, P.P. (2024). Proteomic analysis uncovers clusterin-mediated disruption of actin-based contractile machinery in the trabecular meshwork to lower intraocular pressure. bioRxiv.","DOI":"10.1101\/2024.02.16.580757"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kall\u00f3, G., Zaman, K., Potor, L., Hendrik, Z., M\u00e9hes, G., T\u00f3th, C., Gergely, P., T\u0151zs\u00e9r, J., Balla, G., and Balla, J. (2024). Identification of protein networks and biological pathways driving the progression of atherosclerosis in human carotid arteries through mass spectrometry-based proteomics. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252413665"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Jassim, A.H., Nsiah, N.Y., and Inman, D.M. (2022). Ocular hypertension results in hypoxia within glia and neurons throughout the visual projection. Antioxidants, 11.","DOI":"10.3390\/antiox11050888"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"110143","DOI":"10.1016\/j.exer.2024.110143","article-title":"Neuroprotective effect of Sigma-2 modulator CT2074 in a mouse model of ocular hypertension","volume":"249","author":"Donkor","year":"2024","journal-title":"Exp. Eye Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Prokai, L., Zaman, K., Nguyen, V., and Prokai-Tatrai, K. (2020). 17\u03b2-Estradiol delivered in eye drops: Evidence of impact on protein networks and associated biological processes in the rat retina through quantitative proteomics. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12020101"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/1044-0305(94)80016-2","article-title":"An approach to correlate tandem mass spectral data of peptides with amino acid sequences in a protein database","volume":"5","author":"Eng","year":"1994","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1021\/ac025747h","article-title":"Empirical statistical model to estimate the accuracy of peptide identifications made by MS\/MS and database search","volume":"74","author":"Keller","year":"2002","journal-title":"Anal. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4646","DOI":"10.1021\/ac0341261","article-title":"A statistical model for identifying proteins by tandem mass spectrometry","volume":"75","author":"Nesvizhskii","year":"2003","journal-title":"Anal. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1074\/mcp.M500084-MCP200","article-title":"Comparison of label-free methods for quantifying human proteins by shotgun proteomics","volume":"4","author":"Old","year":"2005","journal-title":"Mol. Cell. Proteom."},{"key":"ref_51","unstructured":"Proteome Software, Inc. (2026). Scaffold DDA User Guide Version 7.0, Proteome Software, Inc.. Available online: https:\/\/cdn.proteomesoftware.net\/user_guides\/scaffold_dda_user_guide.pdf."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5496","DOI":"10.1021\/pr500473n","article-title":"PSEA-Quant: A protein set enrichment analysis on label-free and label-based protein quantification data","volume":"13","author":"Rauniyar","year":"2014","journal-title":"J. Proteome Res."},{"key":"ref_53","unstructured":"QIAGEN (2025). Tutorials: Understanding the p-Value of Overlap Statistic in IPA, QIAGEN. Available online: https:\/\/tv.qiagenbioinformatics.com\/video\/19605716\/understanding-the-p-value-of."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/nbt.2839","article-title":"ProteomeXchange provides globally coordinated proteomics data submission and dissemination","volume":"32","author":"Deutsch","year":"2014","journal-title":"Nat. Biotechnol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T11:38:55Z","timestamp":1786361935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":54,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167153"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167153","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}