Nicholas A. Delamere, Professor and Head, Dept. of Physiology; Professor, Dept. of Ophthalmology & Vision Science, University of Arizona will be delivering a seminar on “A Form of Control: TRPV4 Channels in the Eye” on Wednesday, February 21st at 12:00 Noon in the Moran Eye Center auditorium.
Abstract: Lens transparency requires precise maintenance of ion and water content (homeostasis), something that is difficult to achieve because of the unique properties of lens cells. The seminar will discuss how a particular type of ion channel, TRPV4, acts as a sensor in a remote control mechanism that makes homeostasis possible. The case will be made that lens TRPV4 is activated by mechanical forces. It will be argued that TRPV4 activation works like a switch that opens connexin hemichannels, causing the lens to release signaling molecules that adjust Na,K-ATPase activity in its epithelium monolayer. The significance to human well-being is that cataract is frequently associated with failed homeostasis. In a broader context, the seminar will review TRPV4 expression in other parts of the eye. The ciliary body also uses TRPV4 to sense and respond to mechanical stimuli, perhaps to adjust the driving force for aqueous humor secretion.
Glaucoma is the main cause of irreversible blindness in the world. In most common types of the disease, the optic nerve is damaged by an increase in intraocular pressure (IOP) which blocks fluid drainage through canals in the eye. There is currently no cure, however, the disease can be treated by lowering IOP. Unfortunately, all IOP-lowering drugs that in the market today target the secondary drainage pathway which mediates only 5-15% of fluid outflow. Therefore, the main goal in glaucoma research has been to identify targets in the primary outflow pathway mediated through the trabecular meshwork tissue. David Krizaj’s group at the Moran Eye Institute (University of Utah School of Medicine) has done just that.
In a paper just published in Scientific Reports, they identify TRPV4, a mechanosensitive ion channel, as the main trabecular target of increased IOP. This highly collaborative project combined genetic, molecular, whole animal approaches with bioengineered nanoscaffold models of glaucoma and drug discovery to show that activation of the channel mimics the trabecular changes in glaucoma whereas elimination of the TRPV4 gene or systemic exposure to TRPV4 inhibitors protected mice from the disease. In collaboration with Glenn Prestwich’s group in Medicinal Chemistry at the University of Utah, the team synthesized new eye drops which lowered IOP to levels seen in control mice. By targeting the primary outflow pathway, this study promises to bring new, effective cures that complement current glaucoma treatment. The primary authors of the study are Dr. Dan Ryskamp, Amber Frye and Dr. Tam Phuong.