Feasibility of a mouse model of myopia

描述(由申请人提供)：近视仍然是一个严重的健康问题，与高度近视相关的病理并发症的患病率和发病率不断上升。利用近视的猴子模型，我们找到了近视基因调控的证据，并确定了几个以前未知的候选基因，这些基因定位在与人类近视有关的染色体位置。在猴子模型中对这些基因的进一步表征是有限的，因为对猴子基因组的控制操作是不可能的。小鼠基因组计划的重大进展和控制基因组操作的成熟技术使小鼠成为一个非常有吸引力的物种，可以用来表征这些基因并研究它们在出生后眼睛可塑性中的作用。然而，目前还缺乏关于视觉形式剥夺对小鼠眼睛的影响的确凿数据。检测小鼠眼睛对形式剥夺反应的放大的困难可归因于三个主要因素：i)缺乏系统的方法来优化形式剥夺的视觉条件；ii)没有考虑到常用小鼠品系之间的遗传差异；iii)用于测量视觉形式剥夺时眼睛尺寸变化的技术分辨率不足，预计这种变化非常小。我们的长期目标是确定在出生后发育过程中控制眼睛大小的遗传网络的特征。这个R21应用程序的目标是开发一种近视的小鼠模型。将被检验的中心假设是，小鼠出生后的眼睛生长受到视觉输入的调节，而且这种调节的程度取决于遗传背景。为了实现我们的目标，我们将追求两个特定的目标：1)确定最有利于C57BL/6J小鼠[实验性近视]发展的视觉条件；2)分析遗传[背景]在小鼠对视觉形式剥夺的眼睛反应中的作用。我们将在常用的小鼠品系中分析不同视觉条件下漫射器引起的视觉形式剥夺对眼睛的影响。高分辨率核磁共振将被用来非侵入性地监测眼睛尺寸的时间变化。将测量视网膜周边干细胞的增殖指数，以估计视网膜生长。这项拟议的研究意义重大，因为它将导致开发出一种迫切需要的近视小鼠模型。这样的模型将使后续使用转基因小鼠技术和先进的分子生物学对小鼠出生后眼睛可塑性的分子遗传学研究成为可能，而这在目前是不可能的。这类分子遗传学研究有望提供有关遗传网络的关键信息，这些网络参与了出生后发育过程中视觉输入对眼睛大小的调节。公共卫生相关性：拟议的研究有望导致近视小鼠模型的开发和表征。这些知识可以通过近视小鼠模型获得，最终可以导致开发出控制和改变出生后眼睛生长的药物手段。结合早期诊断，这将有助于医护人员治疗和预防近视。

DESCRIPTION (provided by applicant): Myopia continues to be a significant health problem with increasing prevalence and high morbidity related to pathological complications associated with high myopia. Using a monkey model of myopia, we found evidence for genetic regulation of myopia and identified several previously unknown candidate genes localized to chromosomal loci linked to human myopia. Further characterization of these genes in the monkey model is limited because controlled manipulation of the monkey genome is not possible. Significant progress in the mouse genome project and established technology for controlled manipulation of the genome makes the mouse a very attractive species where to characterize these genes and study their role in postnatal eye plasticity. However, there is currently a lack of conclusive data regarding the effect of visual form deprivation on the mouse eye. Difficulty of detecting an enlargement of the mouse eye in response to form deprivation can be attributed to three main factors: i) absence of a systematic approach to the optimization of the visual conditions for form deprivation; ii) failure to take into account genetic differences among commonly used mouse strains; and iii) insufficient resolution of the techniques used to measure the changes in the dimensions of the eye upon visual form deprivation, which are expected to be extremely small. Our long-term goal is to characterize the genetic network that regulates the size of the eye during postnatal development. The objective of this R21 application is to develop a mouse model of myopia. The central hypothesis that will be tested is that postnatal eye growth in mice is modulated by the visual input, and that the extent of such modulation depends on the genetic background. To achieve our objective we will pursue two specific aims: 1) Identify visual conditions most conducive to the [development of experimental myopia] in C57BL/6J mice; 2) Analyze role of the genetic [background] in the eye response to the visual form deprivation in mice. We will analyze the effect of visual form deprivation induced by diffusers on the eye under various visual conditions in commonly used mouse strains. High-resolution MRI will be used to non-invasively monitor temporal changes in dimensions of the eye. Proliferation index of the stem cells at the retinal periphery will be measured to estimate retinal growth. The proposed research is significant, because it will lead to development of an urgently needed mouse model of myopia. Such model will enable subsequent molecular genetics studies of postnatal eye plasticity in mice using transgenic mouse technology and advanced molecular biology, which are not currently possible. Such molecular genetics studies are expected to provide critical information about genetic networks that are involved in the regulation of the size of the eye by the visual input during postnatal development. PUBLIC HEALTH RELEVANCE: The proposed studies are expected to lead to development and characterization of a mouse model of myopia. The knowledge, which can be acquired using a mouse model of myopia, can ultimately lead to development of pharmacological means to control and modify postnatal eye growth. Combined with early diagnosis, this will help healthcare professionals to treat and prevent myopia.