The overall goal of proposed research is to gain further knowledge of the of the physiology and pharmacology of aqueous outflow in the human eye. Enhanced understanding of the basic mechanism(s) underlying normal outflow physiology may lead to greater insight into the pathogenesis of primary open angle glaucoma (POAG). Although, the monkey eye in vivo has been a valuable model in understanding basic concepts of outflow physiology, the recent concern over the use of primates in biomedical research dictates the need for acceptable alternatives to animal experimentation. Furthermore, the monkey eye is not an optimal model, since monkeys rarely if ever develop POAG. The experimental system to be used in these studies is the perfused human outflow tissue model. This newly developed model involves placement of the eviscerated (e.g. lens and uveal tissue are removed) anterior corneoscleral shell with attached trabecular meshwork (TM) onto a specialized perfusion apparatus. The TM and associated outflow tissues are perfused with culture medium at a physiologically-relevant perfusion pressure in a 5% C02 environment at 37 degree C. Under these conditions, the perfused TM is similar to the human outflow system in vivo for several days with regard to morphology as well as functional parameters. Of considerable interest is the finding that epinephrine increases outflow facility in the perfused TM model. This finding illustrates the potential importance of this model in the study of aqueous outflow dynamics, since this is the only in vitro system in which an epinephrine-induced outflow facility increase has been demonstrated.
The specific aims of this proposal are: 1) to further characterize the perfused TM model; 2) to define the mechanism of action of the epinephrine-induced facility increase as well as investigate the effects of other """"""""trabecular acting"""""""" drugs; and 3) to define morphological correlates of physiological findings. The ability to study the epinephrine responsive human outflow tissues for a period of several days along with the opportunity to establish a model which serves as an alternative to animal testing clearly points to the potential importance of his model in investigating the biology of the outflow pathway system.
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