**1. Introduction**

Glaucoma is one of the leading causes of irreversible blindness worldwide [1]. A gradual loss of retinal ganglion cells (RGCs) result in degeneration of the optic nerve head and visual field loss. Glaucoma is an age-related disease with a strong genetic basis. The risk of developing glaucoma significantly increases after age 40 [2,3]. An estimated 79.6 million people worldwide will have glaucoma by 2020 [1]. Patients with mutations in glaucoma-associated genes are more likely to develop juvenile-onset and early adult-onset glaucoma. In any case, early detection of glaucoma is essential to effectively manage the progression of the disease by preventing further loss of RGCs. Despite many years of research in this field, the precise cause(s) of RGC death remain unknown. The pathophysiology of glaucoma is complicated as environmental, genetic, and even stochastic factors all contribute to the pathology of glaucoma. Also, both the posterior segment, where the RGCs are located, and the anterior segment of the eye play key roles in the disease.

Glaucoma can be classified as being primary, secondary, or congenital. These groups can then be further categorized to be open-angle or closed-angle, depending on the anterior chamber angle. In closed-angle glaucoma, the angle between the iris and the cornea is closed resulting in obstruction of aqueous humor flow. Primary glaucoma is non-syndromic and is not associated with any underlying condition. Primary congenital glaucoma is a rare form of glaucoma present at birth or within the first two years after birth. Glaucoma that develops as a result of an underlying ocular or systemic condition or eye injury is categorized as secondary glaucoma. Pseudoexfoliative glaucoma is an example of secondary glaucoma whereby fibrillar

© 2013 Ito and Walter; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

extracellular material deposits and accumulates in various ocular tissues, predisposing the patient to developing glaucoma.

to increased resistance at the TM are thought to result in elevated IOP, which is a major risk

Genetics and Environmental Stress Factor Contributions to Anterior Segment Malformations and Glaucoma

http://dx.doi.org/10.5772/54653

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**Figure 1. Schematic diagram of aqueous humor flow pathway**. Aqueous humor is produced by the ciliary body in the posterior chamber and then flows into the anterior chamber. The majority of the aqueous humor will be drained from the eye via the trabecular pathway through the trabecular meshwork (TM) and Schlemm's canal. The rest of the aqueous humor is drained via the uveoscleral pathway. Increased resistance occurs when the TM and Schelmm's canal malfunctions. This disruption in aqueous humor outflow leads to increased intraocular pressure (IOP), which is a major

Aqueous humor is drained from the eye by two distinct outflow pathways: the trabecular (aka conventional) pathway and the uveoscleral (aka unconventional) pathway. The uveoscleral pathway is an IOP-independent pathway in which the aqueous humor leaves the anterior chamber by passing through the ciliary muscle bundles into the supraciliary and suprachor‐ oidal spaces and eventually into the sclera [11,12]. Direct measurement of the percentage of aqueous humor leaving the human eye via the uveoscleral pathway has proven to be difficult [13]. There appears to be great variation between individuals with values ranging from 36% to 54% in healthy young subjects [14,15]. The percentage of aqueous humor leaving the eye via the uveoscleral pathway decreases with age with values ranging from 4% to 46% in older subjects [15,16]. Thus, as aging progresses, a larger portion of aqueous humor is drained via

Despite the individual variations, it is generally accepted that in humans, the majority of aqueous humor is transported through the TM via the trabecular pathway. Disruption of aqueous humor drainage through the trabecular pathway is thought to be the major contri‐ buting factor to alteration of IOP. The TM is a multi-layered tissue located in the anterior chamber angle. From the anterior chamber the aqueous humor passes through the multiple layers of the TM: the uveal meshwork, the corneoscleral meshwork, and the juxtacanalicular meshwork (also known as the cribriform plexus). Each layer consists of a central connective tissue (aka beam) surrounded by an outer endothelial layer. Connecting fibrils tightly connect

factor for developing glaucoma [10].

risk factor for developing glaucoma.

the trabecular pathway.

Primary open angle glaucoma (POAG) is a common type of glaucoma where the iridocorneal angle is unobstructed. Although POAG can occur in patients with normal intraocular pressure (IOP), sometimes referred to as normal-tension glaucoma, elevated IOP is a major risk factor of developing POAG. IOP is dependent on proper flow of aqueous humor from the site of production in the posterior chamber to the site of drainage in the anterior chamber of the eye. The anterior chamber structures that function in regulating the drainage of aqueous humor from the eye are the trabecular meshwork (TM) and Schlemm's canal. Disruptions of the aqueous humor flow pathway are predicted to result in elevated IOP.

In this chapter, the recent advances in research regarding the contribution of the TM in maintaining proper IOP will be reviewed. An overview of the anterior chamber drainage structures, the TM and Schlemm's canal, and how these structures maintain the aqueous humor outflow pathway will be provided. Also, the changes that occur in the TM during the normal aging process and in the glaucoma phenotype will be compared. Then, the specific types of stresses that TM cells are exposed to, mainly mechanical, oxidative, and phagocytic stresses, and the effects these stresses have on gene expression will be examined. Recent advances in technology have enabled the analysis of global gene expression profiles. These analyses have revealed that signal transduction pathways play an important role in the cellular adaptive response to environmental stresses. Finally, the effect that environmental stresses have on glaucoma-associated genes will be considered.
