Mechanisms of Ocular Morphogenesis The anterior segment

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DESCRIPTION (provided by applicant): The development and the function of the anterior segment of the eye are important factors in many diseases that affect the eye. Among the most common of these diseases is glaucoma, an optic nerve neuropathy that is often associated with intraocular pressure. In the United States, glaucoma is the second leading cause of blindness, first among African Americans. Hence, an understanding of mechanisms that lead to glaucoma are essential to allow early detection and effective treatment of this progressive and debilitating disease. Recently, we have determined that mutations in the LIM-homeodomain transcription factor LMX1B cause a congenital disease caused nail patella syndrome. This disease affects the development of the limbs and results in renal failure and early onset open angle glaucoma. This insight has allowed us to begin to investigate the underlying molecular and genetic mechanisms leading to congenital glaucoma. By studying the mouse ortholog of human LMX1B, we have determined that lmx1b is expressed in and required for development of tissues that regulate intraocular pressure, linking lmx1b to ocular development and disease. One function of lmx1b in the eye may be to regulate the production of the extracellular matrix. We have also found that lmx1b is not only expressed during eye development, but is also highly expressed in the adult cornea, trabecular meshwork, and iris, suggesting that lmx1b may have important functions in these tissues. To test the hypotheses that lmx1b is expressed in a subset of the cranial mesenchyme, the neural crest, and required in that tissue, we will employ methods of conditional gene targeting in mice. We will extend these studies to test the hypothesis that lmx1b is required for trabecular meshwork formation in adult mice and that lmx1b functions in the adult to regulate important aspects of corneal and trabecular meshwork function. Using these conditionally engineered lmx1b mutant mice, we will explore morphological and molecular changes that accompany selective inactivation of lmx1b in tissues of the eye. These studies will enrich our understanding of molecular mechanisms that contribute to ocular diseases in human, especially glaucoma. Furthermore, these studies will suggest novel diagnostic and therapeutic approaches for the detection and treatment of glaucoma-induced blindness.