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

眼睛生长、正视眼和感光器间视黄醇结合蛋白 (IRBP)

• 批准号: 8439134
• 负责人: John M Nickerson
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439134
• 关键词: ARHGEF5 gene; Accounting; Affect; Age; Apoptosis; Appearance; Binding; Biological; Biology; C57BL/6 Mouse; Cell Death; Cells; Cessation of life; Choroid; Clinic; Data; Development; Drug Targeting; Epidemic; Etiology; Eye; Eye Development; Fatty Acids; Figs - dietary; Functional disorder; Gatekeeping; Gene Expression; Genetic; Growth; Image; Inner Nuclear Layer; Knock-out; Knockout Mice; Lead; Learning; Length; Location; Mediating; Messenger RNA; Mitosis; Movement; Mus; Myopia; Nuclear; Opsin; Pharmaceutical Preparations; Phenotype; Photoreceptors; Play; Population; Positioning Attribute; Prevention; Process; Property; Protein Deficiency; Proteins; Research; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinoids; Rhodopsin; Role; Sclera; Shapes; Signal Transduction; Staging; Testing; Time; Vision; Visual; Vitreous Chamber; Workload; base; deprivation; effective therapy; expectation; experience; interstitial retinol-binding protein; mRNA Expression; mouse model; new therapeutic target; novel; outer plexiform layer; postnatal; precursor cell; prevent; protein expression; public health relevance; research study; response; retinal rods; visual cycle

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.

描述（由申请人提供）：IRBP长期以来被认为在视觉周期中起作用，因为其类维生素A结合特性及其定位于感光器间空间。然而，IRBP mRNA和蛋白质的表达先于视蛋白的表达和感光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。从这个异常，我们推测，早期IRBP基因表达是重要的发展。在测试这一假设时，我们意外地发现IRBP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，眼睛开始异常生长。这意味着IRBP在控制眼睛生长中的作用，即使没有基于视觉的信号。此外，我们发现IRBP KO小鼠缺乏正确的发育修剪和视网膜内核层（INL）细胞（包括内杆）的运动，表明IRBP在视网膜细胞命运中起作用。最后，我们发现IRBP缺乏导致视杆细胞光感受器变性。我们建议测试近视的发展是否导致这种变性，或者是否单独的变性是由IRBP缺乏引起的。一个简单而有组织的集中实验，测试与合理的工作量的假设提出了两个目标。这些是：目标1。检测在P7-P10的关键时间窗内，KO小鼠的光感受器间间隙（IPS）中IRBP蛋白的缺失可唯一归因于近视的预测，以及是否可通过在相同的关键时间窗内将IRBP恢复到其在IPS中的正确位置来预防近视。目标2.测试在不存在IRBP的情况下观察到的近视是否是后续视网膜变性（RD）所必需的，或者与近视病因无关的IRBP的缺乏是否是RD的原因。