A Potential Target Site To Decrease Outflow Resistance
Principal Investigator
Project Goals
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.
Project Summary
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.
Progress Updates
Aqueous humor is produced by the ciliary body cells in the back of the eye (posterior chamber) and flows into the front of the eye (anterior chamber). However, in glaucoma, there is a problem, or a “resistance” to the outflow of this aqueous humor, causing increased intraocular pressure and eventually leading to nerve damage. The reason(s) for increased aqueous humor outflow resistance in primary open angle glaucoma eyes remains unknown. Currently, lack of a thorough understanding of the mechanism responsible for regulating outflow resistance hinders the development of an effective anti-glaucoma therapy aimed at the trabecular meshwork, a “spongy” mesh through which the majority of normal aqueous humor drains.
We are attempting to understand how a rho-kinase protein inhibiting drug, called Y27632, increases aqueous humor drainage (i.e. decreases outflow resistance) in animal and human eyes for future development as an anti-glaucoma treatment. Our previous studies demonstrated that a decrease in outflow resistance after either experimental washout (i.e. the progressive decrease in outflow resistance due to structural change that occurs during prolonged perfusion) or Y27632 treatment coincides with an increase in the available area for aqueous drainage in animal eyes. In our Specific Aim 1, we demonstrated that Y27632 cannot further decrease outflow resistance and increase effective drainage area after washout has been induced in animal eyes. This suggests that Y27632 and washout may target the same site in the aqueous outflow pathway in animal eyes. In our Specific Aim 2, we demonstrated that Y27632 increases outflow after a 3 hour perfusion in donated human eyes. This increase is associated with an increase in effective drainage area in the trabecular meshwork. A study of structural changes that may be responsible for the decrease in outflow resistance and increase in effective drainage area after Y27632 treatment is currently underway.
Publications
Lu Z, Zhang Y, Freddo TF, Gong H. Similar hydrodynamic and morphological changes in the aqueous humor outflow pathway after washout and Y27632 treatment in monkey eyes. Exp Eye Res. 2011 Jun 6. 
First published on: April 14, 2009
Last modified on: November 21, 2024