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.
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.
| Tkatchenko, Andrei V; Tkatchenko, Tatiana V; Guggenheim, Jeremy A et al. (2015) APLP2 Regulates Refractive Error and Myopia Development in Mice and Humans. PLoS Genet 11:e1005432 |
| Tkatchenko, Tatiana V; Shen, Yimin; Braun, Rod D et al. (2013) Photopic visual input is necessary for emmetropization in mice. Exp Eye Res 115:87-95 |
| Bawa, Gurinder; Tkatchenko, Tatiana V; Avrutsky, Ivan et al. (2013) Variational analysis of the mouse and rat eye optical parameters. Biomed Opt Express 4:2585-95 |
| Tkatchenko, Tatiana V; Tkatchenko, Andrei V (2010) Ketamine-xylazine anesthesia causes hyperopic refractive shift in mice. J Neurosci Methods 193:67-71 |
| Tkatchenko, Tatiana V; Shen, Yimin; Tkatchenko, Andrei V (2010) Mouse experimental myopia has features of primate myopia. Invest Ophthalmol Vis Sci 51:1297-303 |
| Tkatchenko, Tatiana V; Shen, Yimin; Tkatchenko, Andrei V (2010) Analysis of postnatal eye development in the mouse with high-resolution small animal magnetic resonance imaging. Invest Ophthalmol Vis Sci 51:21-7 |
