TRPV4 Regulates Calcium Homeostasis, Cytoskeletal Remodeling, Conventional Outflow and Intraocular Pressure

Krizaj glaucoma

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.

Full-Length Axon Regeneration In The Adult Mouse Optic Nerve and Partial Recovery of Simple Visual Behaviors

Friend of Webvision Yves Sauvé sent in this paper by Silmara de Lima, Yoshiki Koriyama, Takuji Kurimoto, Julia Teixeira Oliveira, Yuqin Yin, Yiqing Li, Hui-Ya Gilbert, Michela Fagiolini, Ana Maria Blanco Martinez, and Larry Benowitz that documents regeneration of the optic nerve in the adult mouse, a potentially substantial breakthrough in therapeutic recovery of vision lost through disease or trauma.

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Missing optomotor head turning reflex in the DBA/2J mouse

This paper by Peter Barabas, Wei Huang, Hui Chen, Christopher L. Koehler, Gareth Howell, Simon W.M. John, Ning Tian, René C Rentería and David Križaj is an outcome of an attempt to follow glaucoma progression in the DBA/2J mouse model of a naturally occurring, late onset form of glaucoma.  Ideally, a non-invasive technique should be used and in this case, they used a device to take advantage of the optomotor head turning reflex to assess progressive loss of vision.  This reflex is very similar to the involuntary rotation of the eye in response to a rotating visual stimulus and it is present in all animals from fish to mammals (including humans).  Interestingly, the DBA/2J strain was found to utterly lack this reflex.

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Effect of General Anesthetics on IOP in Elevated IOP Mouse Model

Elevated intraocular pressure (IOP) is the best recognized risk factor for the pathogenesis of glaucoma and the extent of retinal ganglion cell (RGC) degeneration in glaucoma is closely correlated with the extent of IOP elevation.  Therefore, accurately and reliably measuring IOP is critical in investigating the mechanism of pressure-induced RGC damage in glaucoma.  However, IOP is typically measured under general anesthesia in most studies using mouse models and many anesthetics affect the IOP measurements in both human and animals. Continue reading “Effect of General Anesthetics on IOP in Elevated IOP Mouse Model”