Feasibility of a mouse model of myopia

近视小鼠模型的可行性

• 批准号: 7895600
• 负责人: ANDREI V. TKATCHENKO
• 金额: $ 19万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895600
• 关键词: Accounting; Animal Model; Bromodeoxyuridine; Candidate Disease Gene; Chickens; Data; Development; Dimensions; Early Diagnosis; Eye; Eye Development; Eyeglasses; Failure; Frozen Sections; Future; Generations; Genes; Genetic; Genome; Goals; Growth; Health; Health Professional; High Prevalence; Human; Immunohistochemistry; Inbred Strains Mice; Interferometry; Knowledge; Lead; Length; Link; Literature; Magnetic Resonance Imaging; Measurement; Measures; Modeling; Molecular Biology; Molecular Genetics; Monitor; Monkeys; Morbidity - disease rate; Mouse Strains; Mus; Myopia; Optics; Outcome; Pathogenesis; Process; Production; Regulation; Research; Resolution; Retinal; Role; S-Phase Fraction; Stem cells; Techniques; Technology; Testing; Transgenic Mice; Transgenic Organisms; Tupaiidae; Visual; Work; base; deprivation; in vivo; innovation; insight; lens; mouse genome; mouse model; mutant; nonhuman primate; postnatal; prevent; progenitor; public health relevance; response; spatial vision

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.

描述（由申请人提供）：近视仍然是一个重大的健康问题，因为与高近视相关的病理并发症的患病率增加和高发病率。使用近视的猴子模型，我们发现了近视遗传调节的证据，并确定了几个以前未知的候选基因，该基因本地定位于与人近视相关的染色体基因座。猴子模型中这些基因的进一步表征受到限制，因为无法控制猴子基因组的操纵。小鼠基因组项目和建立控制基因组操纵的技术的重大进展使小鼠成为非常有吸引力的物种，可以在其中表征这些基因并研究其在产后眼可塑性中的作用。但是，目前缺乏有关视觉形式剥夺对小鼠眼睛的影响的结论性数据。难以检测响应形式剥夺的小鼠眼的扩大可能归因于三个主要因素：i）缺乏系统的方法来优化视觉条件以形式剥夺； ii）未考虑常用小鼠菌株之间的遗传差异； iii）用于测量视觉形式剥夺时眼睛尺寸的变化的技术的分辨率不足，这些技术预计将非常小。我们的长期目标是表征调节产后发育过程中眼睛大小的遗传网络。该R21应用程序的目的是开发近视的鼠标模型。将要测试的中心假设是，小鼠的产后眼睛生长受视觉输入调节，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的目标：1）确定最有利于[实验近视的发展] C57BL/6J小鼠的视觉条件； 2）分析遗传[背景]在小鼠视觉形式剥夺的眼反应中的作用。我们将分析在常用小鼠菌株中各种视觉条件下，扩散器在眼睛上引起的视觉形式剥夺的影响。高分辨率MRI将用于非侵入性监测眼睛尺寸的时间变化。将测量视网膜外围的干细胞的增殖指数以估计视网膜生长。拟议的研究很重要，因为它将导致急需的近视小鼠模型的发展。这种模型将使用转基因小鼠技术和晚期分子生物学对随后的分子遗传学研究对小鼠的产后眼可塑性进行研究，目前是不可能的。预计，这种分子遗传学研究将提供有关遗传网络的关键信息，这些信息在产后发育过程中通过视觉输入来调节眼睛的大小。公共卫生相关性：预计拟议的研究将导致近视小鼠模型的发展和表征。可以使用近视的小鼠模型获得的知识最终会导致制定药理手段以控制和修改产后眼睛的生长。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。