In 1873, German ophthalmologist Theodor Leber postulated that elevated intraocular pressure (IOP) in the glaucomatous eye resulted from increased outflow resistance to aqueous humor drainage. It is widely accepted that the likely site of outflow resistance resides between the juxtacanalicular region of the trabecular meshwork (TM) and the inner wall of the Schlemm canal, but identification of the regulatory mechanisms and molecules within this area has been elusive.
Increase in TM cell contractility, permeability, and different forms of stress are a few of the mechanisms believed to increase outflow facility in primary open-angle glaucoma (POAG). Understanding the pathophysiology of outflow resistance in normal and POAG eyes is essential for the identification of key molecules that can be used as novel therapeutic targets.
Michael P. Fautsch, Ph.D., of the Department of Ophthalmology at Mayo Clinic in Rochester, Minnesota, and his laboratory team are conducting several innovative studies to identify the molecular events involved in IOP modulation, including identification of novel prostaglandin analog cell signaling targets and aqueous humor flow through the conventional outflow pathway.
Prostaglandin analogs such as latanoprost are among the first line treatments for lowering IOP, but their mode of action at the molecular level is unknown. Until recently it was thought that prostaglandin analogs acted solely through the uveoscleral pathway.
Using an ex vivo anterior segment human eye culture model developed at Mayo Clinic, researchers have demonstrated that prostaglandin analogs increase outflow facility through the conventional or trabecular outflow pathway in addition to the uveoscleral pathway.
Using several prostaglandin analogs, multiple primary TM cell lines, and different treatment durations, Dr. Fautsch's research team has identified several proteins involved in prostaglandin analog signaling. One of these proteins is calcipressin, an inhibitor of calcineurin, a serine-threonine phosphatase protein involved in several calcium-dependent cellular signaling pathways. Treatment with cyclosporine, an inhibitor of calcineurin activity, increased outflow facility in the ex vivo anterior segment human eye culture model, suggesting a role for calcipressin and calcineurin in IOP control.
Ongoing studies aim to identify regulatory proteins downstream to calcipressin and calcineurin. The goal is to identify these molecules and develop therapeutics to regulate their activity, leading to better control of IOP.
Classical understanding of the aqueous humor outflow pathway focuses on homogenous fluid movement through the TM. This focus is partly due to lack of human models and the ability to visualize fluid movement in real time.
Mayo Clinic researchers have found that aqueous flow through the TM is not uniform but is increased in regions of the TM underneath the collector channels. These preferential fluid flow regions are associated with expanded TM (specifically the juxtacanalicular tissue) found directly under collector channels.
Mayo researchers are using 3-dimensional micro-computed tomography to study the conventional outflow pathway as a functional unit. This imaging modality enables identification of the collector channel location, size, and associated episcleral veins down to 2-micrometer resolution.
Preliminary work indicates that the orifice size of collector channels in POAG eyes may be reduced by as much as 50% compared with normal collector channel orifices. This finding is important because the reduction in collector channel orifice size would have a profound effect on outflow resistance. Determining whether the change in orifice size is a cause or effect in glaucoma is a new direction for Dr. Fautsch's research team.
It has been more than 130 years since Dr. Leber's astute recognition that elevated IOP is the result of increased outflow resistance to aqueous drainage. New approaches are beginning to dissect the molecular and anatomic features associated with POAG. Many questions, however, still require answers. Researchers at Mayo Clinic currently work to: