Glaucoma is a complex group of diseases which if left untreated result in irreversible blindness. Identification and characterization of aberrant molecular pathways causing glaucoma will contribute to improved drug therapies for people with glaucoma. One approach for identifying molecular events resulting in glaucoma is through genetic approaches using mice. We have identified 2 independently segregating loci, isa and ipd, that cause secondary glaucoma involving iris stromal atrophy, pigment dispersion, elevated IOP, and optic nerve excavation in the inbred DBA/2J (D2) mouse strain. The identity of isa and ipd are unknown, although preliminary experiments implicate Tyrp1 as a candidate for isa. This study proposes to identify, characterize, and functionally confirm the identity of the isa and ipd genes. A high-resolution genetic map will be created for ipd using an intersubspecific genetic backcross carried out to at least 2000 meioses. Physical YAC and BAC contigs will be used to identify cDNAs within the smallest interval determined to contain the ipd gene. Candidates for ipd will be molecularly characterized and functionally examined for relevance to the D2 glaucomatous phenotypes. The same approach will be taken for isa with initial priority given to functional testing of Tyrp1 via transgenic experiments. Identification of the isa and ipd genes will identify components of pathological pathways likely to be involved in human disease and contribute to a molecular understanding of glaucoma.
