The candidate's long-term aims is to understand non-visual photoreception in the eye, and its relationship to modulation of circadian rhythmicity and ocular immune function. Retinal degenerate mice, although blind, retain functional ocular photoreception for two phenomena: the resetting of the behavioral circadian clock, and the modulation of ocular inflammation (ACAID). This finding suggests the existence of ocular photoreceptors outside rods and cones. The identity of the photoreceptor(s) underlying these phenomena are unknown, but as both phenomena share a common spectral sensitivity, a single photoreceptor molecule is implicated. A new family of flavin-based blue-light photoreceptors - the cryptochromes - have been described, and are expressed in the eye. These molecules have been implicated in the light-resetting of the circadian clock in plants, and are well conserved in mammals. Their role in the modulation of immune function or circadian rhythmicity in mammals is unknown. Identification of this phototransduction pathway has broad import in understanding both the ocular contributions to circadian rhythms and their disease states, such as insomnia and seasonal depression, and in understanding the mechanisms of pathogenesis of ocular inflammation. The candidate proposes to study the molecular biology and genetics of this protein family in the sponsor's laboratory. He will (1) determine the temporal and spatial expression of the cryptochromes in the murine eye and suprachiasmatic nucleus of the brain, (2) determine the gene structure of members of the cryptochrome family, and (3) generate loss- and gain-of-function mutations in the members of this family and study their effects on circadian rhythm entrainment and modulation of intraocular immune response.
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