A Potential Target Site To Decrease Outflow Resistance
The goal of this study is to better understand the mechanisms involved in the regulation of aqueous outflow resistance in non-human and human eyes and to determine whether the connectivity between the inner wall of Schlemm's canal and underlying matrix in a portion of the eye, termed the trabecular meshwork, can be targeted to reduce outflow resistance, thus lowering intraocular pressure (IOP) in human eyes as it occurs in non-human eyes.
The reason(s) for increased aqueous humor outflow resistance in primary open angle glaucoma (POAG) eyes remains unknown. Currently, lack of a thorough understanding of the mechanism responsible for regulating aqueous humor outflow resistance hinders the development of effective anti-glaucoma therapy aimed at “trabecular outflow”, through which the majority of normal aqueous outflow exits the eye. In our preliminary studies of non-human eyes we found that the available area for aqueous outflow increases when outflow resistance decreases after short term perfusion with a cell structure disrupting agent, Y27632. This suggests a relationship between the available area for aqueous outflow and outflow resistance, which was regulated by a structural change in the aqueous drainage system. Similar changes were not found in cadaver human eyes under a similar experimental condition. We are attempting to understand the mechanism causing these structural changes in non-human eyes. We will take the non-human results and use this as a means to induce similar changes in human eyes in order to develop a new anti-glaucoma treatment. We will use our newly developed methods to study the following Specific Aims:
1) To determine whether a type of drug called Y27632, a Rho-kinase inhibitor and the cell-structure disrupting agent, can further decrease outflow resistance after the structural change has been induced after long-term perfusion ( washout effect) in non-human eyes;
2) To determine whether a similar structural change can be induced to decrease outflow resistance using different experimental conditions in human eyes;
3) To determine whether decrease in aqueous humor outflow resistance under two experimental conditions (long-term perfusion and treatment by Y27632) share a similar mechanism.