Glaucoma is one of the leading causes of blindness in America, and affects over 15 million individuals. Loss of vision is caused by degeneration of the optic nerve, often accompanied by elevated intraocular pressure. There is a large genetic component to this disease, but the specific genes involved are not yet known. Current treatments are aimed at slowing vision loss by reducing intraocular pressure, but do not address the molecular basis of the disease. The goal of this project is to investigate differential gene expression in the trabecular meshwork, in order to identify genes that affect the drainage of fluid, and in turn, intraocular pressure. We hypothesize that the abnormal functioning of trabecular meshwork tissue in patients with primary open angle glaucoma (POAG) is associated with altered patterns of gene expression in this tissue. We will use Serial Analysis of Gene Expression (SAGE) to profile transcription patterns in trabecular meshwork from POAG patients as well as from young (20-40 years) and age-matched (50-70 years) controls. Genes whose expression levels are significantly up- or down-regulated in affected individuals will be investigated as candidate genes for POAG. We will also investigate genes whose expression levels changes significantly with age in normal individuals. These genes will be mapped, providing an excellent resource for future positional cloning of disease genes that affect the trabecular meshwork. Candidate genes will then be tested for association with POAG by family-based association analysis. This double screen-differential expression in affected tissue and statistical association with disease-will provide a powerful mechanism for the identification of candidate susceptibility genes. The most promising candidates will then be characterized at the molecular level and screened for mutations and polymorphisms. The identification of POAG susceptibility genes could provide the basis for diagnostic tests and lead to earlier detection of POAG and a greatly improved prognosis for the millions of patients affected with this debilitating disease.
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