IRBP has long been assumed to function in the visual cycle because of its retinoid binding properties and its localization to the interphotoreceptor space. However, IRBP mRNA and protein expression precede opsin expression and the last mitosis of photoreceptor precursor cells, that is, well before IRBP would function in the visual cycle. From this anomaly we hypothesize that early IRBP gene expression is important in development. In testing this hypothesis, we unexpectedly find that IRBP knockout (KO) mice develop high myopia, with aberrant eye growth starting after P7 and before P10, well before eyes open. This implies a role for IRBP in controlling eye growth even without vision-based signaling. Additionally, we find that IRBP KO mice lack correct developmental pruning and movement of retinal inner nuclear layer (INL) cells, including inner rods, suggesting that IRBP plays a role in retinal cell fate. Finally, we find that IRBP deficiency results in rod photoreceptr degeneration. We propose to test whether the development of myopia results in this degeneration, or whether the degeneration separately results from IRBP deficiency. A simple and organized set of focused experiments that test the hypotheses with sensible workload are proposed in two aims. These are:
Aim 1. To test the predictions that myopia can be attributed uniquely to the absence of the IRBP protein in the interphotoreceptor space (IPS) of the KO mouse in a critical time window of P7-P10, and whether myopia can be prevented by restoring IRBP to its correct location in the IPS in the same critical time window.
Aim 2. To test whether the myopia observed in the absence of IRBP is required for the subsequent retinal degeneration (RD) or whether the absence of IRBP, separate from myopia etiology, is responsible for the RD.
Myopia affects 25% to 70% of the world's population. It has reached epidemic proportions. We need more effective treatments for myopia, especially profound myopia. Significance: The surprising finding of highly myopic IRBP knockout (KO) mice suggests an entirely different function from what was thought about IRBP. How IRBP may control emmetropia and non-vision mediated development of eye size and shape is vitally important and timely. A mechanistic study of etiology of myopia in the IRBP KO mouse contributes to this need. Impact: We will learn basic biology of when IRBP is required for normal eye growth. Cause and effect are discovered: Does IRBP directly cause myopia and independently cause RD? Or does this myopia directly result in RD? The project may identify IRBP as a target or sink for drug treatments to prevent myopia.
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