We recently generated a knockout mouse (RBP -/-) that totally lacks serum retinol-binding protein (RBP). RBP -/- mice, at the time of weaning, have greatly impaired vision. This is evidenced by electroretinograms (ERGS) taken for wild type and RBP -/- littermates at weaning. Histologic analysis indicates that the neural retinas of RBP -/- mice are not different from those of wild type mice, suggesting that the impaired vision defect observed for RBP -/- mice does not arise from abnormal eye development. By six months of age, the RBP -/- mice acquire normal ERGs and normal vision. We wish to gain understanding of the impaired vision phenotype of RBP -/- deficient mice through the studies proposed in this application. RBP plays a role in delivering all-trans-retinol from hepatic or tissue stores to the eye. Based on data obtained from RBP -/- mice, we hypothesize that the eye, or more specifically the RPE, slowly acquires retinol through a process that involves uptake of recently ingested dietary retinol. This slow acquisition of retinol by the RPE parallels the acquisition of vision by RBP -/- mice. We propose to test this hypothesis in specific aims 1 and 2 of this project. In addition, RBP is expressed in the retinal pigment epithelium (RPE) and it has been proposed that this RPE-expressed RBP may play a role in transporting retinoids within the eye. We also hypothesize that the lack of RBP synthesis within the RPE contributes to the impaired vision of RBP-deficient mice. This hypothesis will be tested in specific aim 3 of the project. The role of RBP in human vision is poorly understood. Recently, two female siblings with what appears to be faulty RBP synthesis due to heterozygous mutations in the RBP gene were found to have only mildly defective vision (reduced dark adaptation and slightly reduced acuity), but not blindness, in the face of serum RBP levels below the detection limits of these investigators (< 0.2 uM) (Selliger et al., Invest. Ophthalmol. Vis. Sci., 1999, 32:3-11.). This data obtained through the study of these human patients, like our data obtained from study of RBP-deficient mice, suggests that RBP is not the sole source through which the eye acquires retinol. Using unique animal models, we are proposing to investigate the pathways important for retinol delivery to the eye and within the eye. These studies will provide fundamental new information about the role(s) of RBP in vision. This information will be directly relevant to humans and human disease.
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