{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T03:54:51Z","timestamp":1774410891268,"version":"3.50.1"},"reference-count":85,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T00:00:00Z","timestamp":1655769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["EY022077"],"award-info":[{"award-number":["EY022077"]}]},{"name":"National Institutes of Health","award":["EY028616"],"award-info":[{"award-number":["EY028616"]}]},{"name":"National Institutes of Health","award":["EY026177"],"award-info":[{"award-number":["EY026177"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glaucoma is a multifactorial disease leading to irreversible blindness. Primary open-angle glaucoma (POAG) is the most common form and is associated with the elevation of intraocular pressure (IOP). Reduced aqueous humor (AH) outflow due to trabecular meshwork (TM) dysfunction is responsible for IOP elevation in POAG. Extracellular matrix (ECM) accumulation, actin cytoskeletal reorganization, and stiffening of the TM are associated with increased outflow resistance. Transforming growth factor (TGF) \u03b22, a profibrotic cytokine, is known to play an important role in the development of ocular hypertension (OHT) in POAG. An appropriate mouse model is critical in understanding the underlying molecular mechanism of TGF\u03b22-induced OHT. To achieve this, TM can be targeted with recombinant viral vectors to express a gene of interest. Lentiviruses (LV) are known for their tropism towards TM with stable transgene expression and low immunogenicity. We, therefore, developed a novel mouse model of IOP elevation using LV gene transfer of active human TGF\u03b22 in the TM. We developed an LV vector-encoding active hTGF\u03b22C226,228S under the control of a cytomegalovirus (CMV) promoter. Adult C57BL\/6J mice were injected intravitreally with LV expressing null or hTGF\u03b22C226,228S. We observed a significant increase in IOP 3 weeks post-injection compared to control eyes with an average delta change of 3.3 mmHg. IOP stayed elevated up to 7 weeks post-injection, which correlated with a significant drop in the AH outflow facility (40.36%). Increased expression of active TGF\u03b22 was observed in both AH and anterior segment samples of injected mice. The morphological assessment of the mouse TM region via hematoxylin and eosin (H&amp;E) staining and direct ophthalmoscopy examination revealed no visible signs of inflammation or other ocular abnormalities in the injected eyes. Furthermore, transduction of primary human TM cells with LV_hTGF\u03b22C226,228S exhibited alterations in actin cytoskeleton structures, including the formation of F-actin stress fibers and crossed-linked actin networks (CLANs), which are signature arrangements of actin cytoskeleton observed in the stiffer fibrotic-like TM. Our study demonstrated a mouse model of sustained IOP elevation via lentiviral gene delivery of active hTGF\u03b22C226,228S that induces TM dysfunction and outflow resistance.<\/jats:p>","DOI":"10.3390\/ijms23136883","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T21:55:19Z","timestamp":1655848519000},"page":"6883","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["A Novel Mouse Model of TGF\u03b22-Induced Ocular Hypertension Using Lentiviral Gene Delivery"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-0165","authenticated-orcid":false,"given":"Shruti V.","family":"Patil","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramesh B.","family":"Kasetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Cameron","family":"Millar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7823-2595","authenticated-orcid":false,"given":"Gulab S.","family":"Zode","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/S0140-6736(17)31469-1","article-title":"Glaucoma","volume":"390","author":"Jonas","year":"2017","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The number of people with glaucoma worldwide in 2010 and 2020","volume":"90","author":"Quigley","year":"2006","journal-title":"Br. 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