Intraocular Pressure

High IOP typically causes glaucoma, but the factors causing high IOP are not clearly defined. To understand the initial processes leading to glaucoma, it is important to identify the genes that cause elevated IOP. We have studied IOP in mice carrying mutated genes that are expressed in ocular tissue involved in aqueous humor production and drainage. Although these studies identified genes that control IOP, none of the tested mutations elevated IOP to levels that cause glaucoma. Thus, we are currently focusing on identifying and characterizing new mutants with greater elevations of IOP. We are characterizing several interesting mutants that appear to affect different pathways.

 

Genetics of glaucoma in DBA/2J mice

In pigmentary glaucoma, iris cells are damaged, resulting in dispersal of iris pigment into the ocular drainage structures, and this induces high IOP. DBA/2J mice develop a form of pigmentary glaucoma caused by mutations in the glyocoprotein (transmembrane) nmb gene, Gpnmb, and the tyrosinase-related protein 1 gene, Tyrp1. Since both genes encode melanosomal proteins, we hypothesized that their mutation somehow allows toxic intermediates of pigment production to leak from melanosomes, causing iris disease and pigmentary glaucoma. Supporting this, albino and hypopigmentation mutations prevent disease development. This suggests that mutant melanosomal protein genes may contribute to human pigmentary glaucoma, and that therapeutic strategies to decrease pigment production may be beneficial. Adding a further layer of understanding, our experiments demonstrate that bone marrow-derived cells and inflammatory processes contribute to the depigmenting iris disease. Current experiments suggest that the Gpnmb mutation of DBA/2J disturbs ocular immune privilege and allows immune cells to attack the iris and propagate the iris disease that induces glaucoma.

Ongoing experiments focus on the nature of the immune system's involvement in this glaucoma. Not all individuals with pigment dispersion develop high IOP. Thus, we will also assess the possibility that differences in immune responses determine whether the dispersed pigment induces high IOP. We have produced a useful tool for these studies by backcrossing the Gpnmb and Tyrp1 mutant alleles from DBA/2J into the C57BL/6J strain. This mutant C57BL/6J congenic strain develops the same iris disease as DBA/2J mice but is much less susceptible to IOP elevation. We are studying this strain differnce in susceptibility to IOP elevation. An understanding of the genes and pathways that are involved may lead to new treatments to prevent IOP elevation in human glaucoma.

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