BIOLOGY OF TRABECULAR RESPONSE TO LASER TRABECULOPLASTY

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Laser trabeculoplasty (LTP) is a commonly used treatment for open-angle glaucoma, which is frequently effective in reducing elevated intraocular pressure by enhancing aqueous humor outflow. Its mechanism remainS only partially understood. The objective of this research project is to develop a cohesive molecular and cellular understanding of this mechanism. Several discrete cellular events occur following LTP, including early DNA replication in a population of cells localized to the trabecular insert, migration of these cells to repopulate open areas of the meshwork, and localized expression of stromelysin and other members of a family of matrix metalloproteinases in the juxtacanalicular and insert regions of the meshwork. The matrix metalloproteinases initiate extracellular matrix remodelling and turnover thus may be important in aqueous humor outflow regulation. Specific objectives include: 1) the purification and characterization of the factor, which is released by LTP and which can induce these cellular and molecular events. The LTP-factor's production and mode of action will be evaluated. Use of this factor as a substitute for actual LTP, which is moderately destructive to the meshwork, would be therapeutically advantageous. 2) The metalloproteinase and inhibitor expression will be evaluated in terms of levels of active proteinases and their role in trabecular extracellular matrix remodelling as initiated by LTP. Extensive trabecular extracellular matrix and tissue remodelling by these enzymes may be central to the mode of LTP action. 3) The trabecular cells of the insert and juxtacanalicular regions respond strongly to LTP; differences between this sub-population of trabecular cells and the much less responsive corneoscleral and uveal meshwork cells will be evaluated. Methods to modulate trabecular repopulation by these cells will be evaluated, due to the therapeutic potential this poses. 4) The effects of perfusion culture on the LTP responses and the effects of LTP on perfused culture flow rates will be determined. Changes in these effects in response to metalloproteinase inhibition will be evaluated. Taken together, these studies will enhance our understanding of this frequently- used treatment for open-angle glaucoma and may produce significant possibilities for improved therapies for this family of common blinding disease entities.