Elevated intraocular pressure is a major risk factor in glaucoma, the most common cause of irreversible blindness worldwide. The long-term objectives of this research are to determine endogenous mechanisms that contribute to the physiological regulation of intraocular pressure, and to define factors that contribute to the pathophysiological pressure rise in glaucomatous individuals. This application focuses specifically on actions of the kallikrein/kinin system that we have found to increase outflow facility within the anterior chamber. We have also observed a synergistic interaction between bradykinin and PGE2 signaling in trabecular meshwork cells that may contribute significantly to the regulation of outflow resistance. The working hypothesis is that kinins, produced locally within the eye, act in an autocrine/paracrine fashion to regulate conventional outflow by modulating secretion of matrix regulating proteins in cells of the trabecular meshwork. It is also proposed that PGE2, produced by trabecular meshwork cells in response to kinins, facilitate kinin actions to enhance aqueous outflow. To test these ideas, studies will be performed in isolated perfused bovine and human anterior segments and in primary cultures of bovine and human trabecular meshwork cells. Experiments are proposed 1) to determine receptor mechanisms of bradykinin actions to increase outflow facility in the anterior segment, 2) to examine kinin signaling mechanisms that regulate MMP/TIMP secretion and activation in trabecular meshwork cells, and the relationship of these actions to the control of outflow facility, and 3) to determine the mechanism of kinin/PGE2 signal interactions in trabecular cells, and the contribution of these interactions to the regulation of outflow facility. The studies proposed will serve to define endogenous mediators and signaling pathways that regulate conventional outflow facility in the eye, and should provide insight into how dysfunction in these systems may lead to elevation of intraocular pressure.
| Webb, Jerry G; Yang, Xiaofeng; Crosson, Craig E (2011) Bradykinin activation of extracellular signal-regulated kinases in human trabecular meshwork cells. Exp Eye Res 92:495-501 |
| Webb, Jerry G; Yang, Xiaofeng; Crosson, Craig E (2009) Expression of the kallikrein/kinin system in human anterior segment. Exp Eye Res 89:126-32 |
| Webb, Jerry G; Husain, Shahid; Yates, Phillip W et al. (2006) Kinin modulation of conventional outflow facility in the bovine eye. J Ocul Pharmacol Ther 22:310-6 |
