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)

基本信息

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
项目类别：
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

项目摘要

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）：长期以来，IRBP一直假定在视觉循环中起作用，因为其视网膜类似结合特性及其与phototeceptor空间的定位。然而，IRBP mRNA和蛋白质表达先于Opsin表达和光感受器前体细胞的最后有丝分裂，也就是说，在IRBP在视觉周期中起作用之前。通过这种异常，我们假设早期的IRBP基因表达在发育中很重要。在检验这一假设时，我们出乎意料地发现，IRBP敲除（KO）小鼠的近视发育高，眼睛在P7之后和P10之前开始，在眼睛睁开之前。这意味着即使没有基于视觉的信号传导，IRBP也在控制眼睛生长方面发挥了作用。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）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缺乏会导致Rod Photoreceptr变性。我们建议测试近视的发展是否导致这种退化，或者退化是由于IRBP缺乏而单独导致的。在两个目标中提出了一组简单而有条理的集中实验，以明智的工作量测试假设。这些是：目的1。要测试近视可以独特地归因于P7-P10的关键时间窗口中KO鼠标中的IRBP蛋白（IPS）中缺乏IRBP蛋白，以及是否可以通过将IRBP恢复到同一关键的时间窗口中的IPS中的IPS位置来防止近视。目的2。要测试在没有IRBP的情况下观察到的近视是随后的视网膜变性（RD）是否需要的，或者是否缺乏与近视病因分开的IRBP是造成RD的原因。