A mechanistic understanding of corneal pathobiology and the development of therapeutic strategies for the treatment of connective tissue disorders

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The cornea is the transparent window at the front of the eye and is its main focussing element. To fulfil its role it has to be transparent, strong and precisely shaped. Transparency and strength are controlled by the collagen fibrils that make up the cornea, and by the small molecules between them. Shape is also controlled by the collagen arrangement, but we have now discovered a complex system of small elastic fibres that we believe helps to restore shape when the cornea is distorted, for example as blood is pumped round the body, during blinking or after eye rubbing. These properties of the cornea are controlled at different structural levels: collagen molecules form fibrils, which in turn form larger structures called lamellae, which are then stacked up to form the tissue itself. Elastic fibres that contain the protein elastin are concentrated around the edge of the cornea in the form of sheets, which we have shown are connected across the human cornea by fine filaments rich in proteins called fibrillins. We want to test our hypothesis that this arrangement allows distortion and recovery mainly at the edge of the cornea, maintaining the shape of the central cornea that controls the focussing of the incoming light. From previous work by us and others, we know a lot about why the cornea is transparent and are beginning to understand the arrangement of collagen lamellae and elastic fibres that gives rise to the cornea's shape and thus its focusing abilities. However, the contribution of different elements of the structure to the overall function is still not known and, until we elucidate this, it will not be possible to understand why, in numerous diseases of the cornea, or after different types of surgery on the cornea, transparency, strength and/or shape are abnormal and vision is lost or very blurred. We have pioneered the use of several sophisticated techniques to study the cornea at every structural level from the molecules upwards: x-ray scattering, serial block face scanning electron microscopy and two photon fluorescence light microscopy. We propose now to build equipment that will allow us to measure which constituents of the structure change when the cornea is distorted by known forces, either during its normal functioning or due to disease and/or surgery. We will also explain how lamellae are arranged to provide form and strength, how the elastic fibres are structured in different parts of the cornea, and what role they play in health and disease. We showed that abnormalities of the elastic fibres occur in corneal diseases such as keratoconus, and we will test our idea that they play a role in other diseases of the eye, such as glaucoma. In addition, we will investigate treatments for corneal disorders, for example by developing new chemical crosslinking methods. To address the world-wide shortage of donor corneas, biological artificial corneas are being developed. However, for corneal replacements to function normally, we must fully understand how nature utilises the constituents of a tissue to achieve its vital properties. This means elucidating the exact relationships between its various components and its function, including how cells communicate with other cells during development, wound healing and tissue regeneration. In the case of the cornea, the knowledge that we will obtain by discovering the exact relationship between its various structural components and its function is crucial for our understanding of corneal transparency and biomechanical stability as related to corneal development, surgical manipulation and implantation, and tissue engineering. Finally, we will demonstrate how cornea is an excellent model system for connective tissues more generally, by collaborating with other groups around the world, using our new techniques to aid our understanding of function/dysfunction in other parts of the body.