GLAUCOMATOUS DAMAGE TO TM CELLS
Elevated IOP is one of the primary risk factors in the development of glaucoma. The trabecular meshwork (TM) is a critical tissue involved in the outflow of aqueous humor and regulation of IOP. Changes in the extracellular matrix (ECM) environment in the TM can alter the ability of aqueous humor to properly drain from the anterior chamber. The involvement of TGF-β2 signaling pathways in the regulation of the ECM in the TM has been extensively studied. Recent evidence has implicated toll-like receptor 4 (TLR4) in the regulation of ECM and fibrogenesis in other tissues such as liver, kidney, lung and skin. My laboratory has discovered that mutation in TLR4 rescues TGFβ2-induced ocular hypertension in mice. This discovery is a direct result of a careful mouse strain characterization utilizing our mouse model of TGFβ2-induced ocular hypertension. Based on these results, we have developed a novel hypothesis, involving crosstalk between TGFβ2 and TLR4 signaling. These studies could provide new targets to lower IOP and further explain the mechanisms involved in the development of glaucomatous TM damage.
IDENTIFICATION OF NEW MOUSE MODELS OF GLAUCOMA
Several different types of mouse models of glaucoma have been developed such as spontaneous genetic models, transgenic models, as well as various inducible models to elevate IOP including physically damaging the outflow pathway, occluding the TM, treating with glucocorticoids, or using viral vectors encoding glaucoma associated transgenes to transduce the TM. Although there are many advantages to each of these models, there is still not an ideal model of glaucoma as many either do not mimic all aspects of human glaucoma, have variable phenotypes between animals, or are labor intensive and involve extensive breeding and aging of the animals. My laboratory aims to identify a mouse model of glaucoma that mimics human glaucoma, is homogenous in response, and provides phenotypes without extensive breeding/aging. We have a candidate model in the laboratory now that we are actively characterizing for elevated IOP, RGC damage, and damage to the optic nerve and optic nerve head.