The retina converts light into electrical signals through a series of biochemical steps collectively referred to as phototransduction. Via the optic nerve, these signals reach the brain, where visual perception occurs. Rod and cone photoreceptor cells in the retina respond to light throughout our lives because they continuously regenerate visual (retinoid) cycle proteins and a light-sensitive chromophore. Disabling mutations in the genes encoding these proteins are among the main causes of blinding diseases in humans and other factors affect vision as well. Studies in mice indicate that age-related decreases in rod cell function cannot be explained by rod cell loss, abnormal retinal plasticity or any signs of retinal disease. Based on experiments in mice, age-related deterioration of dark adaptation is ameliorated by artificial cis-retinoid treatment. This finding probably relates to the age-related decline in human vision manifested by dramatic slowing of rod-mediated dark adaptation attributable to delayed rhodopsin regeneration. In addition, anomalous reactions in the retinoid cycle can cause progressive retinal changes similar to human age-related retinal degeneration, which are prevented by retinoid cycle inhibitor. So the long-term objective of our research is to elucidate the molecular basis of age related rod and cone photoreceptor cell dysfunction and develop rational pharmacological interventions to prevent this pathology. We propose three thematically linked specific aims to address this issue: (1) Characterize age-related retinal dysfunction in A/J mice, which exhibit early onset, progressive age-related retinal dysfunction similar to aging humans. (2) Assess age-related retinal dysfunction in A/J mice treated with either 9-cis-retinoids or retinylamine or combination of both drugs. (3) Identify A/J mouse chromosomes containing causative genes for age-related retinal dysfunction.
A/J mice exhibit spontaneous early-onset progressive age-related retinal dysfunction similar to aging humans, and are therefore an excellent model to study the underlying mechanisms of ARD. We will use a simplified genetic approach to determine which chromosome(s) in the A/J mouse are likely to contribute to this deficit. We also will test the response of these mice to two artificial retinoids that improve other visual disorders by affecting the retinoid (visual) cycle in photoreceptor cells of the retina.
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