Secker, G. (2009) Characterisation of the corneal epithelium and stem cell niche using models of PAX6 deficiency. Doctoral thesis, UCL (University College London).
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The corneal epithelium is continuously renewed by a population of stem cells that reside in the corneo-scleral junction, otherwise known as the limbus. These limbal epithelial stem cells (LESC) are imperative for corneal maintenance, with deficiencies resulting in in-growth of conjunctival cells, neovascularisation of the corneal stroma and eventual corneal opacity and visual loss. One such disease that has traditionally been thought to be due to LESC deficiency is aniridia, a pan-ocular congenital eye disease due to PAX6 heterozygosity. Corneal changes or aniridia related keratopathy (ARK) seen in aniridia are typical of LESC deficiency, however, the pathophysiology behind ARK is still ill defined. Recent studies, utilising heterozygous Pax6 mouse models suggests that ARK is not solely due to LESC deficiency. Current theories suggests it may be caused by a deficiency in the stem cell niche and adjacent corneal stroma leading to abnormal differentiation of epithelial cells, with an altered wound healing response also playing a role (Ramaesh et al., 2005a, Li et al., 2008). The ultimate goal of biological research is to further the understanding of disease mechanisms with aim to develop improved therapies, therefore this thesis examines the pathogenesis of the ARK with this in mind. The difficulties found with the initial assessment of gene replacement therapy in the mouse highlighted the need for further investigation into LESC location and ARK progression. The examination of corneal epithelial label retaining cells indicated an increase in numbers and abnormal location of putative LESC in the heterozygous Pax6 mouse, suggesting these cells may fail to differentiate into progeny cells. Furthermore, analysis of corneal epithelial and fibroblast cells with PAX6/Pax6 down regulation has further established that an abnormal wound healing response may be involved in disease progression. Overall, these studies have highlighted the complexity of the disease and the requirement for further investigation to dissect the mechanisms underlying ARK, providing clues for future directions in therapy development.
|Title:||Characterisation of the corneal epithelium and stem cell niche using models of PAX6 deficiency|
|Additional information:||Authorisation for digitisation not received|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology|
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