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长期以来一直被认为在视觉周期中起作用，因为它的维甲酸结合特性和它在光感受器间空间的定位。然而，IRBP的mRNA和蛋白的表达先于视蛋白的表达和光感受器前体细胞的最后有丝分裂，即IRBP在视觉周期中发挥作用之前很久。根据这种异常，我们推测IRBP基因的早期表达在发育过程中很重要。在检验这一假设时，我们意外地发现IRBP基因敲除(KO)小鼠出现高度近视，眼睛从P7之后到P10之前，甚至在睁开眼睛之前就开始异常生长。这意味着IRBP在控制眼睛生长方面发挥了作用，即使没有基于视觉的信号。此外，我们发现IRBP KO小鼠缺乏正确的视网膜内核层(INL)细胞(包括内杆)的发育修剪和运动，这表明IRBP在视网膜细胞命运中发挥作用。最后，我们发现IRBP缺乏会导致杆状感受器退化。我们建议测试近视的发展是否导致这种退化，或者这种退化是否单独由IRBP缺乏引起。提出了一组简单而有组织的集中实验，以合理的工作量测试假设，目的有两个。目的：1.验证近视可唯一归因于KO小鼠在P7-P10的关键时间窗中光感受器间隙(IPS)中缺少IRBP蛋白的预测，以及是否可以通过在相同的关键时间窗中将IRBP恢复到其在IPS中的正确位置来预防近视。目的2.检测在无IRBP的情况下观察到的近视是否是随后的视网膜变性(RD)所必需的，或者是否在近视病因之外，IRBP的缺失是导致RD的原因。