The overall aim of our research is to develop more effective therapies for treating corneal scarring after trauma or infection. To accomplish this objective, we have focused our attention to the molecular mechanisms responsible for the development of corneal opacification in wound healing. In particular, we will characterize the biological function and the role in corneal wound healing of one important molecule, keratoepithelin (KE), which is found to contain specific point mutations (by this and other laboratories) in patients with visually incapacitating anterior corneal dystrophies. In this study, we plan to create a transgenic mouse model for the human lattice and Avellino corneal dystrophies with KE mutant constructs. We will make two DNA constructs, each of which contains the KE mutant cDNA that corresponds to one of the two human corneal dystrophies, lattice (R124C) and Avellino (R124H) respectively. By using cornea-preferred promoters, we will test the KE constructs first in vitro to examine the expression of the KE mutant protein. These KE mutant constructs will then be injected into mouse embryos and the genotypes of these founder pups examined to confirm the presence of the transgenes. Phenotypically, these transgenic mice will be characterized using slit- lamp biomicroscopy to detect the presence of corneal dystrophies, histologic studies for the amyloid precipitation, and immunohistochemical characterization of the KE deposits. This transgenic mouse model will be valuable in our future corneal wound-healing experiments designed to characterize the biological function of KE, its role in maintaining corneal optical clarity and in wound healing.
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