Identification and Pathology of a Macula-Related Structure in the Mouse Eye

小鼠眼黄斑相关结构的鉴定和病理学

基本信息

批准号：
9761525
负责人：
MARK P KREBS
金额：
$ 20.07万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761525
关键词：
3-Dimensional Age Age related macular degeneration Aging Anatomy Animal Model Animals Area Binocular Vision Blindness Blood Vessels Butterflies Canis familiaris Cell Density Cells Cellular Morphology Choroid Complex Computer software Data Defect Disease Dorsal Drusen Elderly Environmental Risk Factor Exhibits Eye Family suidae Gap Junctions Genes Genetic Geometry Heterozygote Human Image Laboratory mice Lead Lesion Light Link Mammals Mendelian disorder Microscopy Modeling Molecular Morphology Mus Mutant Strains Mice Neurons Pathogenesis Pathogenicity Pathologic Pathology Photoreceptors Pigments Population Primates Process Public Health Publishing Reporting Research Retina Retinal Retinal Cone Risk Site Smoking Stargardt&apos s disease Structure Structure of retinal pigment epithelium Susceptibility Gene Testing Thick Time Tissues Update Vision Vision research Visual impairment Vitelliform macular dystrophy Wild Type Mouse Work age related aged base ciliary artery cost cost effective density disease phenotype disorder of macula of retina fundus imaging ganglion cell genetic variant image registration insight macula macular dystrophy mouse model mutant non-invasive imaging nonhuman primate novel strategies pattern dystrophies prevent retinal rods stem

项目摘要

PROJECT SUMMARY/ABSTRACT Diseases of the macula, a primate-specific retinal specialization that is critical for high acuity vision, are a leading cause of vision loss worldwide. Animal models are essential for resolving macular disease mechanisms and testing treatments. Non-human primates, which are favored as models because they possess a macula, require decades to develop and are costly to maintain. Dogs and pigs have also been considered, but a macula-related structure that recapitulates features of macular disease has been reported only in dogs, and studies of these animals are also limited by time and cost. Laboratory mice can be bred and analyzed much more efficiently than large animals, but their use in macular disease research is often criticized due to the view that mice lack a macula-related structure. In preliminary studies that challenge this view, raised hyaline lesions in the retinal pigment epithelium (RPE) of a homozygous mutant Ctnna1 mouse model of butterfly-shaped pigment dystrophy were distributed in a dorsal band with a temporal bias. A similar band of subtle lesions in or near the RPE was observed with age in fundus images of heterozygous Ctnna1 mutant mice, which have milder disease. This distribution parallels a dorsal-temporal feature of the mouse retina characterized by photoreceptor and ganglion cell density gradients, as in the human macula. The central hypothesis is that this area of the mouse posterior eye constitutes a macula-related retinal specialization that develops lesions under conditions linked to human macular disease. To test this hypothesis, we will 1) determine the topographic distribution of hyaline RPE lesions in homozygous Ctnna1 mutant mice, the structure of the retina in the vicinity of these lesions, and the RPE and retinal structure of the corresponding region in wild-type mice by noninvasive imaging and microscopy; and 2) examine whether subtle RPE lesions occur with a similar topographic distribution in aging heterozygous Ctnna1 mutants and in wild-type mice. To achieve these aims, we will use a new approach to register images of the mouse posterior eye in spherical geometry based on vascular landmarks. These studies are expected to define a macula-related structure in mice that is targeted by gene- and age-dependent pathogenic processes. !

项目摘要/摘要黄斑的疾病是一种灵长类动物特异性的视网膜专业化，对于高敏锐视觉至关重要，是一个全球视力丧失的主要原因。动物模型对于解决黄斑病至关重要机制和测试治疗。非人类灵长类动物，因为他们拥有黄斑，需要数十年的发展，并且维护成本很高。狗和猪也是考虑的，但是已经报道了与黄斑疾病特征的大黄斑相关结构只有在狗中，对这些动物的研究也受到时间和成本的限制。实验室小鼠可以繁殖，并且分析比大型动物更有效，但是它们在黄斑病研究中的使用经常受到批评由于认为小鼠缺乏与黄斑相关的结构。在挑战这种观点的初步研究中纯合突变突变体CTNNA1小鼠模型的视网膜色素上皮（RPE）中的透明病变蝴蝶形色素营养不良分布在具有时间偏置的背带。类似的乐队在杂合CTNNA1突变体的眼底图像中观察到RPE中或附近的细微病变小鼠，患有温和疾病。该分布与小鼠视网膜的背态特征相似如人黄斑中的光感受器和神经节细胞密度梯度的特征。中央假设是，小鼠后眼的这一区域构成了与黄斑相关的视网膜专业化在与人黄斑疾病有关的条件下发展病变。为了检验这一假设，我们将1）确定纯合CTNNA1突变小鼠中透明RPE病变的地形分布，视网膜在这些病变附近的结构，以及相应的RPE和视网膜结构通过非侵入性成像和显微镜在野生型小鼠中的区域； 2）检查是否微妙的RPE病变在衰老的杂合CTNNA1突变体和野生型小鼠中发生相似的地形分布。到达到这些目标，我们将使用一种新方法在球形上注册鼠标后眼的图像基于血管地标的几何形状。预计这些研究将定义与黄斑相关的结构由基因和年龄依赖性致病过程靶向的小鼠。呢