June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Partially closed angle glaucoma model exhibits altered conventional pathway with a preserved uveoscleral pathway
Author Affiliations & Notes
  • Japnit Dham
    Medical Sciences, McMaster University, Hamilton, Ontario, Canada
  • Aftab Taiyab
    McMaster University, Hamilton, Ontario, Canada
  • Fatima Shirazee
    McMaster University, Hamilton, Ontario, Canada
  • Terete Borras
    University of North Carolina System, Chapel Hill, North Carolina, United States
  • Trevor Williams
    University of Colorado, Denver, Colorado, United States
  • Judith A West-Mays
    McMaster University, Hamilton, Ontario, Canada
  • Footnotes
    Commercial Relationships   Japnit Dham None; Aftab Taiyab None; Fatima Shirazee None; Terete Borras None; Trevor Williams None; Judith West-Mays None
  • Footnotes
    Support  NIH R01EY025789
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 4009 – A0351. doi:
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      Japnit Dham, Aftab Taiyab, Fatima Shirazee, Terete Borras, Trevor Williams, Judith A West-Mays; Partially closed angle glaucoma model exhibits altered conventional pathway with a preserved uveoscleral pathway. Invest. Ophthalmol. Vis. Sci. 2022;63(7):4009 – A0351.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Anterior segment dysgenesis involves abnormal development of one or more anterior segment structures, including the trabecular meshwork (TM) and Schlemm’s canal (SC); this increases risk of developing glaucoma due to elevated intraocular pressure (IOP). We have generated a unique mouse model by deleting activating protein-2β (AP-2β) transcription factor from the developing periocular mesenchyme and its derivatives. The resultant mutant shows a partial angle closure and increased IOP. We hypothesize that the uveoscleral pathway remains functional in this model and thus IOP can be reduced through treatment with prostaglandin analogs such as latanaprost (LTP).

Methods : MgpCre+/- mice were bred with tfap2b+/- mice. Male MgpCre+/-;tfap2b+/- offspring were then crossed with female tfap2blox/lox mice to obtain the final offspring, the MgpCre+/-;tfap2b-/lox or AP-2β trabecular meshwork region knockout (TMR-KO) mice, as well as littermate controls. A 40 kDA FITC-conjugated dextran tracer was injected into the anterior segment of mutant and control mice. 0.005% LTP eye drops were used for topical treatment of the eye. The mice were euthanized 10 minutes after injection and eyes were enucleated, fixed, and cryosectioned. RNAscope Hiplex Assay was performed to determine changes in key genes in the mutants that are critical for proper functioning of TM and SC.

Results : In control mice, dextran clumps were observed in the TM region, both with and without LTP treatment (n=6 eyes). This was absent in the mutant mice, likely due to a blocked conventional pathway as demonstrated by previous histological staining. In comparison, dextran was observed along the uveoscleral pathway in the mutants after 5 and 10 minutes of LTP treatment (n=6 eyes). The RNAscope Assay performed in control and mutant mice revealed decreased levels of important SC markers, including Prox1 and Klf4, in the mutant.

Conclusions : Our findings show that while the conventional pathway is blocked in the TMR-KO mutants, the uveoscleral pathway remains functional. Reduction in both Prox1 and Klf4 levels further supports that development of the conventional pathway is altered in the TMR-KO mutants. Since these genes encode pressure-induced transcription factors, it is surmised that lack of aqueous flow through the SC region during development contributed to the phenotype.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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