Gene Discovery in Mouse Models for Secondary Cataracts

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DESCRIPTION (provided by applicant): Epithelial to Mesenchymal Cell Transition (EMT) is one of the major problems following cataract surgery. Lens epithelial cells adherent to the lens capsule can grow and differentiate into mesenchymal cells resulting in posterior capsule opacification (PCO). This process leads to secondary cataracts that have to be treated again. Identification of factors that promote transdifferentiation of the lens epithelial cells is of paramount importance for possible therapies of PCO. Unfortunately, experiments in this field are hindered by the lack of experimental models where the powerful genetic techniques can be applied. We have found that when extracapsular surgery is performed in the mouse, the remaining lens epithelial cells on the capsule proliferate rapidly and fill the bag with normal looking lens fibers. Normal morphology of the "regenerated" lens can also be seen, with established bow regions. The morphology of the regenerated lens depends on the surgery and the integrity of the lens capsule. However, along with the normal differentiation to lens fibers, lens epithelial cells can also transdifferentiate to mesenchymal cells, especially at the early stages of lens regeneration. This lens regeneration mouse model can become, therefore, an indispensable and long-sought animal model to study PCO. Taking advantage of such an animal model system we propose to study global gene expression patterns and gene discovery during the process. In order to achieve this we will examine lens regeneration in mice with mutations in genes important to EMT and PCO. At the same time the ability of these mice to undergo (or not) lens regeneration or EMT will be correlated with gene expression using whole mouse genome microarrays. Expression and roles of key genes will be verified in functional assays using capsular bags. The databases that will be established will be compared with each other and with databases established from developing, adult and cataractous lenses. This research will eventually identify gene patterns of known and novel genes that are involved in EMT and PCO as well as in normal lens fiber differentiation. This research aims to establish new ways for the treatment of secondary cataracts and the elimination of posterior capsule opacification. Also, this research will address the bipotency of lens epithelial cells to undergo EMT, which results in secondary cataracts, or lens fiber differentiation, which is a normal repair process.