COBRE: BIOLOGICAL MECHANISM RESPONSE FOR GLAUCOMA

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glaucoma is the second leading cause of blindness among Americans and the leading cause among African Americans. Pigmentary glaucoma is one of the most common forms of secondary glaucoma. The primary causes of these abnormalities are unknown, and their etiology is poorly understood. At the present time, the medical treatments of pigmentary glaucoma are the non-specific reduction of intraocular pressure (IOP) with aqueous suppressants, laser trabeculoplasty and filtering surgery. Yet, little is known about the molecular/biochemical mechanism(s) underlying this disorder. DBA/2J mouse shares many similarities with pigmentary glaucoma in humans including iris atrophy, pigment dispersion, and peripheral anterior synechiae that are associated with development of elevated IOP, and retinal ganglion cell loss and optic neuropathy. Our previous publication demonstrated that the expression of autoimmune mediator interleukin-18 (IL-18) in the iris/ciliary body and level of IL-18 protein in the aqueous humor of DBA/2J mice are dramatically increased with age. This increase precedes the onset of clinical evidence of pigmentary glaucoma. If increased expression of IL-18 is an important risk factor in the disease susceptibility, a chronic and mild form of subclinical inflammation in addition to mechanical zonular-pigment epithelial interaction could cause iris damage leading to pigment dispersion and eventually glaucoma. Our long-term goal is to understand biological mechanisms responsible for pigmentary glaucoma. We have produced IL-18 deficient DBA/2J mice showing no IL-18 expression in IL-18-/--DBA/2J, intermediate IL-18 expression in IL-18+/--DBA/2J, and high IL-18 expression in IL-18+/+-DBA/2J mice. We will use these mice to test our central hypothesis that the increased expression of IL-18 activates a series of biochemical cascades leading to iris degeneration, pigment dispersion, and finally development of pigmentary glaucomatous phenotype. Aim #1 is designed to test the hypothesis that increased expression of IL-18 is necessary to induce glaucomatous phenotype in the eyes of DBA/2J mice. The extent of iris dystrophy, level of IL-18 expression, elevation of IOP, retinal ganglion cell degeneration and vision function loss will be evaluated and compared among IL-18-/--DBA/2J, IL-18+/--DBA/2J, and IL-18+/+-DBA/2J as well as DBA/2J, IL-18-/--C57BL/6J, and C57BL/6J mice. Aim #2 is designed to text the hypothesis that IL-18 regulates the expression of specific pro-inflammatory cytokines and enzymes via activation of MAPK/NF-kB signaling pathways in the eyes of DBA/2J mice. Aim #3 is designed to test the hypothesis that IL-18 activates apoptotic cascades leading to iris degeneration, pigment dispersion, and glaucomatous damage in the eyes of DBA/2J mice. The intrinsic and extrinsic apoptotic signaling cascades in the iris and in the retina in relationship with the level of IL-18 expression will be examined. Our proposal meets the overall emphasis for research in glaucoma program reported in The National Plan for Vision Research by the National Advisory Eye Council: to identify the biological mechanisms responsible for glaucoma so that improved treatment can be developed. Results from proposed studies in this proposal should improve our understanding of pigmentary glaucoma and will provide foundation for eventually developing improved and targeted treatments to ameliorate this blinding disease.