LUMICAN AND EYE DEVELOPMENT AND FUNCTIONS

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Lumican is a major proteoglycan component of the corneal stroma and believed to play a pivotal role in corneal transparency. In the cornea, transparency is combined with tensile strength by a highly ordered array of collagen fibrils of uniformly thin diameter. Lumican inhibits lateral growth of collagen fibrils in vitro and may have a similar effect on collagen fibril formation in the cornea. The keratan sulfate glycosaminoglycan side chains of lumican retain water and help to maintain interfibrillar spacing necessary for transparency. The molecular interactions underlying lumican's influence on collagen fibrils are poorly understood. The PI preliminary results also indicate that lumican is expressed very early in the developing corneal stroma, implying a potential role for this proteoglycan in corneal development. The purpose of this study is to elucidate lumican's role in the cornea. The first aim is to define the molecular mechanism underlying lumican's interactions with collagen and gain insight into this important aspect of lumican's function in the cornea. this aim will determine the binding kinetics and identify sites on the lumican core protein that are active in collagen-binding and inhibiting lateral growth of fibrils. The second aim is to determine if lumican inhibits cell adhesion to collagen or fibronectin substrates, and thus, likely to regulate mesenchymal cell adhesion/migration during development of the corneal stroma. The third aim is to generate lumican-deficient mice by targeted deletion of the gene for lumican and determine its effect on development of the eye and structure and functions of the cornea. The in vitro experiments proposed in this study will identify functionally important regions of the lumican core protein for future site-directed mutagenesis studies of lumican in vivo. The gene targeted deletion of lumican proposed in this study will, for the first time, address its role in vivo and the overall effect of its absence on the cornea. Generally, the long term objectives are to develop mouse models for corneal dystrophies another connective tissue disorders with altered proteoglycan-collagen matrices.