Ocular Growth, Emmetropia, and Interphotoreceptor Retinoid-Binding Protein (IRBP)

描述（由申请人提供）：IRBP一直被认为在视觉周期中起作用，因为它的类视黄醛结合特性和它在光感受器间隙的定位。然而，IRBP mRNA和蛋白的表达早于视蛋白的表达和光感受器前体细胞的最后一次有丝分裂，也就是说，早于IRBP在视觉周期中发挥作用。根据这一异常，我们假设早期IRBP基因表达在发育中很重要。为了验证这一假设，我们意外地发现IRBP基因敲除（KO）小鼠发生高度近视，在P7之后和P10之前，在眼睛睁开之前就开始异常的眼睛生长。这意味着即使没有基于视觉的信号，IRBP也在控制眼睛生长中发挥作用。此外，我们发现IRBP KO小鼠缺乏视网膜内核层（INL）细胞（包括内杆细胞）的正确发育修剪和运动，这表明IRBP在视网膜细胞命运中起作用。最后，我们发现IRBP缺乏导致杆状光感受器变性。我们建议测试近视的发展是否导致了这种变性，或者这种变性是否单独由IRBP缺乏引起。提出了一套简单而有组织的集中实验，以合理的工作量来验证假设。它们是：目标1。为了验证近视可唯一归因于P7-P10关键时间窗内KO小鼠IPS中IRBP蛋白缺失的预测，以及在同一关键时间窗内将IRBP恢复到IPS中的正确位置是否可以预防近视。目标2。为了检验在IRBP缺失的情况下观察到的近视是否为随后的视网膜变性（RD）所必需，或者IRBP缺失是否与近视病因无关，是导致RD的原因。

DESCRIPTION (provided by applicant): 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.