An integrated experimental and theoretical approach to understanding corneal epithelial maintenance

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Maintenance of the cornea, the transparent front surface of the eye that acts as our window on the world, is necessary for normal vision. There are many ways in which it can get permanently damaged, leading to opacity and potential loss of sight. In spite of intense study by many laboratories, major questions relating to the maintenance of the corneal surface remain. For example, although a large body of evidence exists which implies that stem cells have a major role, the actual location of these stem cells, and to what extent and under what circumstances they are active, remains highly controversial. Similarly, while it is known that cell migration occurs throughout life in the cornea, its importance and even its direction have been disputed. Because maintenance of the corneal surface is fundamental to our eyesight it is essential that we understand the basic biology about how the cornea functions normally and reacts, in the short and long term, to injury.This project will address the significant issues about stem cell localisation and activity, cell production, migration and loss, within the corneal surface epithelium. We will build upon a computer model that we have already developed that potentially explains some of the patterns of cell migration and loss that we have previously observed. We will refine that model using new biological data, and then use it to make testable predictions about how the cornea is maintained normally, how it is affected by ageing and genetic defects and how it responds to injury. We have an array of 'reporter' mice which, because they express fluorescent or other chemical markers in subsets of their corneal epithelial cells, can be used to trace patterns of cell production and migration in the cornea throughout life, starting during gestation and continuing into the ageing adult. Using these mice, we will be able to model genetic abnormalities and corneal injuries that test the predictions of the computer model. The mice will be used to show where the stem cells are localised in the cornea - knowledge that is essential to our understanding of how the epithelium is maintained. They will show how normal patterns of cell production and migration in the corneal surface are changed by injury and genetic defects, and also reveal whether these changes are long or short term. Changes in stem cell activity and migration patterns with ageing will also be determined using these mice - it is known for example that ageing human corneas heal less quickly than those from younger people. The refined model will have lasting benefits, as we will be able to use it to predict how different types of abnormalities occur in different corneal diseases. It will also contribute to reducing future animal experiments. Overall the project will generate key fundamental understanding of the processes that underlie corneal maintenance during normal life. We will be able to determine where the stem cells are, what they do and how replacement cells get to sites of injury. This knowledge will also help us understand why the corneal surface sometimes suffers degeneration and opacification that is difficult to treat. If new insights from our animal studies are applicable to humans this may also improve the management of corneal diseases or complications arising from operations such as laser eye surgery.