TAMOXIFEN-INDUCED KNOCK-OUT OF A RETINAL GENE

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This proposal is designed to provide a diverse and extensive research experience in molecular biology, biochemistry, and electrophysiology that will allow the applicant to develop into a mature scientist-clinician with an outstanding potential to contribute to both academic ophthalmology and basic science research. All components of training are incorporated in the curriculum of the EyeSTAR program based at UCLA. The research project will focus on the generation of tissue- and time- specific modifications in the gene encoding the gamma subunit of cGMP- phosphodiesterase (PDEgamma) by using an inducible knockout system. The entire coding region of the PDEgamma will be flanked by 34-base pair Cre-recombinase recognition sites (loxP) introduced into the gene locus by homologous recombination. After germline transmission, mice Pdeglox1/Pdegtm1 bearing the modified allele will be crossed with mice expressing the Cre-recombinase/steroid hormone receptor fusion protein under the control of the genomic locus of the beta subunit of PDE (Pdeb). The use of Cre-recombinase/steroid hormone receptor fusion protein will allow the regulation of Cre-recombinase activity with exogenously applied steroids. Gaining temporal and spatial control of gene expression is essential for the elucidation of gene function in the whole organism. The proposed studies will develop tools that will ease the deletion of genes from the genome in specific cells and at specific times. Understanding of the mechanisms controlling photoreceptor signaling and degeneration in Pdeglox1/Pdegtm1 mice may help to develop strategies for the prevention or slowing of human retinal dystrophies. Dr. Debora Farber is nationally recognized for her biochemical and molecular biological studies of retinal degenerations, in particular retinitis pigmentosa. Dr. Farber will serve as mentor for the PI'S postdoctoral studies. In addition, UCLA has an outstanding panel of faculty members many of whom have professional relationships with Dr. Farber and can serve as scientific consultants to the PI. The proposed project will be at the cutting edge of current research is an ideal area with which to begin a scientific career. The EyeSTAR program also incorporates three years of clinical training in ophthalmology leading to certification and specialty board eligibility. This intense three-year residency program providers a vast clinical experience in diagnosis and treatment of the complete scope of ophthalmologic problems as well as a number of didactic activities including lectures, special seminars, and attendance at clinical research meetings.