Feasibility of a mouse model of myopia

描述（由申请人提供）：近视仍然是一个重要的健康问题，与高度近视相关的病理并发症相关的患病率和高发病率不断增加。使用猴子近视模型，我们发现了近视遗传调控的证据，并确定了几个先前未知的候选基因定位于与人类近视相关的染色体位点。在猴模型中对这些基因的进一步表征是有限的，因为不可能对猴基因组进行受控操作。小鼠基因组计划的重大进展和基因组控制操作的成熟技术使小鼠成为一个非常有吸引力的物种，在那里可以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，目前缺乏关于视觉形式剥夺对小鼠眼睛的影响的结论性数据。难以检测响应于形觉剥夺的小鼠眼睛增大可归因于三个主要因素：i）缺乏优化形觉剥夺的视觉条件的系统方法; ii）未能考虑常用小鼠品系之间的遗传差异;和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，所述变化预计是非常小的。我们的长期目标是描述在出生后发育过程中调节眼睛大小的遗传网络。该R21应用的目的是开发近视小鼠模型。将要检验的中心假设是，小鼠出生后眼睛的生长受到视觉输入的调节，并且这种调节的程度取决于遗传背景。为了实现我们的目标，我们将追求两个具体目标：1）确定最有利于C57 BL/6 J小鼠[实验性近视发展]的视觉条件; 2）分析遗传[背景]在小鼠视觉形觉剥夺的眼睛反应中的作用。我们将分析在各种视觉条件下，在常用的小鼠品系中，扩散器诱导的视觉形觉剥夺对眼睛的影响。高分辨率MRI将用于无创监测眼睛尺寸的时间变化。将测量视网膜周边处的干细胞的增殖指数以估计视网膜生长。这项研究意义重大，因为它将导致急需的近视小鼠模型的开发。这种模型将使随后的分子遗传学研究出生后的眼睛可塑性的小鼠使用转基因小鼠技术和先进的分子生物学，这是目前不可能的。这些分子遗传学研究有望提供有关遗传网络的关键信息，这些遗传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：预计拟议的研究将导致近视小鼠模型的开发和表征。可以使用近视小鼠模型获得的知识可以最终导致控制和改变出生后眼睛生长的药理学手段的发展。结合早期诊断，这将有助于医疗保健专业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.