The trabecular meshwork of the eye is the principal site of outflow resistance to the aqueous humor. A protein called myocilin has been linked genetically to some forms of glaucoma. We have studied the expression of this protein in sections of the trabecular meshwork as well as in human trabecular meshwork cells grown in tissue culture. This protein has a molecular mass of around 57kDa. The mRNA levels of myocilin increase in cultured cells treated with dexamethasone, heat or oxidative stress. Gene arrays have been done to determine additional components in trabecular meshwork that have altered expression levels when treated with dexamethasone. A number of primary cultures from various individual donors have been studied and compared with organ cultured whole trabecular meshwork from donor eyes. The results obtained with the gene arrays are currently being verified with other techniques on several selected genes. We are also looking at the effects of prostaglandin derivatives, latanoprost acid and prostamide, on the trabecular meshwork. These compounds, which are very similar in structure, cause reductions in intraocular pressure and are medications currently used for glaucoma treatment. It is thought that latanoprost acid works on the uvealscleral outflow pathway but not on the trabecular meshwork. The prostamide is reported to work on both outflow pathways. The exact mechanisms by which these compounds work are not known and the long-term effects on the anterior segment of the eye are unclear. There do not appear to be major morphological changes in cells treated with these drugs although at least one protein has increased expression with the prostamide treatment. Gene array technology will be used to investigate the changes that these two drugs cause within the trabecular meshwork and the ciliary muscle. Our long-term goal is to develop a selective gene transfer system to assist cells in the outflow pathway reduce the resistance to aqueous humor outflow and thereby stop visual field loss. Two components from the trabecular meshwork that might be important in regulating outflow both in normal and in diseased conditions have been identified and studied. These proteins influence extracellular matrix turnover. We believe overexpression of some of these proteins might be beneficial in the trabecular meshwork to reduce intraocular pressure. These candidates should be useful in gene therapy of glaucoma.
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