The Role of Podosomes in Regulating Eye Pressure

Using transgenic mice with a conditional mutation, we aim to test how a small finger-like projection of cells (i.e. podosomes) may be a key regulator of aqueous humor outflow and intraocular pressure.

Despite progress, the exact molecular location for aqueous humor outflow resistance remains unknown. We propose that SH3PXD2B is a key protein, functioning within podosomes, that defines this location. We have generated a transgenic mouse strain with a conditional variant of Sh3pxd2b. Specific Aim 1 uses this new resource to test whether disrupting podosomes via Sh3pxd2b mutation results in elevated intraocular pressure and glaucoma. Specific Aim 2 will use the resource in a different approach that results in an over-abundance of Sh3pxd2b, which we hypothesize may lower intraocular pressure.

Knowing the exact cellular machinery that naturally regulates aqueous humor outflow is of obvious importance for glaucoma. Finding ways to study these physiological events has not been so obvious. The innovation of our current proposal derives from a uniquely engineered mouse resource which will allow us the temporal and spatial specificity needed to test the role of podosomes in a physiologically relevant context.

Podosomes are a cellular structure that is used by many kinds of cells in instances when a localized regulation of the extracellular matrix is needed. Because of their broad importance, screens for molecules influencing podosome activity have already been performed. Thus, if a role for podosomes in regulation of intraocular pressure can be established, it would immediately suggest new compounds worthy of consideration in treating glaucoma.