Cytoskeletal and Junctional Modulation of Aqueous Outflow

The proposed research is directed towards the development of novel approaches for the treatment of glaucoma, based on the pharmacological modulation of cell-cell (C-C) and cell-extracellular matrix (C-ECM) adhesions and the associated cytoskeleton. The underlying rationale is that cell adhesions in the trabecular meshwork and the inner wall of Schlemm’s canal contribute, directly or indirectly, to outflow resistance by forming part of the outflow barrier. Thus, controlled perturbation of such adhesions may lead to an increase in flow and consequently to reduction in intraocular pressure. The primary model system which we intend to use will consist of cultured bovine aortic endothelial cells which form conspicuous C-C and C-ECM adhesions, and an elaborate microfilament system. Preliminary studies, carried out in collaboration with Dr. P. Kaufman indicated that changes in the adhesion of these cultured cells, induced by specific kinase inhibitors and cytoskeletal drugs, provided an excellent prediction for increase in outflow facility in living monkeys. The compounds to be tested include several inhibitors of serine/threonine- and tyrosine-specific protein kinases and drugs which affect the structure of the actin-rich microfilament system. In these studies we will define the effective drug concentrations, and determine the kinetics of the effect and its molecular and subcellular targets. Following these studies with cultured cells we intend to examine the in vivo effect of junction-modulating compounds and evaluate their potential use as glaucoma drugs.