The exact structural determinants of the aqueous humor outflow barrier are not completely understood, but the extracellular matrix of the trabecular meshwork appears to contribute a major component. Primary open angle glaucoma is a common, blinding, disorder of increased resistance to trabecular outflow and anomalies of the extracellular matrix in glaucomatous eyes have been observed. This proposal is designed to examine biochemically the extracellular matrix of the trabecular meshwork. It is based upon two working hypotheses: 1) that extracellular glycosaminoglycans (GAGs), as components of more complex proteoglycan aggregates, are major determinants of trabecular outflow resistance and 2) that this resistance is regulated by biochemical messengers which may come from the aqueous humor and/or from the ciliary body. These studies will investigate the structure and biochemical regulation of the primate trabecular GAGs, proteoglycans and certain extracellular glycoproteins that constitute the extracellular matrix. The dynamics of radiolabeled precursor incorporation into the trabecular extracellular matrix will be investigated in human and nonhuman primate corneoscleral explant organ culture. Biochemical and morphological criteria will be used to define this system and evaluate biosynthetic and degradative pathways. Immunohistochemical methods will be used to localize the proteoglycans and certain extracellular glycoproteins (laminin, fibronectin and type IV collagen) within the trabecular meshwork. Biochemical methods will be used to complete the purification and characterization of the trabecular proteoglycans and to study their aggregate forms. In previous studies, a factor(s) in aqueous humor and the ciliary body has been shown to modulate the biosynthesis and/or turnover of trabecular GAGs. This regulation will be evaluated, the modulator purified or identified and its action upon the trabeculum investigated.
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