**8. Sensors of TM cells**

overload of the proteasomal machinery with damaged proteins. Caballero *et al*. observed an increase in oxidized proteins in the older donors [90]. Accumulation of oxidized protein is not

The accumulation of lipid peroxidation products in the TM is suggested to also contribute to proteasomal dysfunction [107]. Lipid peroxidation occurs when a ROS attacks a polyunsatu‐ rated fatty acid, thus initiating the lipid peroxidation chain reaction, which results in highly reactive aldehydes [108,109]. Lipid peroxidation products interact with protein, which results in modification to the protein structure and activity [109]. Accumulation of lipid peroxidation end products have been observed in many neurodegenerative diseases including Alzheimer's disease [110] and Parkinson's disease [111]. In glaucoma, an increase in lipid peroxidation end products, including diene and triene conjugates, and Schiff's bases, were observed in glau‐ comatous TM tissue (n=17) and aqueous humor (n=16) compared to age-matched controls (n=13 and n=17, respectively) [91]. In addition, Fernandez-Durango *et al.* measured increased levels of the lipid peroxidation mediator, malondialdehyde (MDA), in the aqueous humor of patients with terminal cases of POAG (n=38) compared to the cataract control group (n=48) [92]. Accumulation of lipid peroxidation products is predicted to have severe consequences on the TM by modifying proteins such as calpain-1. The calpains are a family of calciumactivated non-lysosomal cysteine proteases. In glaucomatous TM tissue, aggregated and degraded calpain-1 is present, but calpain-1 activity is lower compared with normal TM tissue [107]. In the TM of glaucomatous eyes, the lipid peroxidation products isolevuglandins, specifically iso[4]levuglandin E2, modifies calpain-1, thereby inhibiting calpain-1 activity. Although the physiological function of calpain-1 in the TM remains to be elucidated, calpain-1 modified by isolevuglandins is more prone to form larger aggregates. One of the major consequences of this modification is a disruption in the proteasomal machinery. This type of malfunction of the proteasomal machinery appears to be specific to the TM and does not occur in the posterior segment of the eye. Thus, accumulation of oxidative stress-related biomole‐ cules along with a decrease in proteasomal activity with age perpetuates a vicious cycle that

the only biomolecule detrimental to proteasomal function.

38 Glaucoma - Basic and Clinical Aspects

is postulated to greatly hinder cell survival.

stress in TM cells.

**7. Global change in gene expression in response to stress**

As reviewed in the previous sections, cells of the TM are exposed to a variety of environmental stresses. The stresses can vary in form (mechanical, phagocytic, and oxidative), magnitude, and duration (acute or chronic). The antioxidant system and the proteolytic system are effective cellular defense mechanisms that protect cells. Recent advances in technology have shown that a change in the global gene expression profile is another major part of a cell's adaptive response to stress (reviewed in [112]. The change in gene expression profile in response to stress has revealed that signal transduction pathways are a necessary means of integrating complex signals and propagating these signals to effectors. In the next section, we will examine the specific sensors and signal transduction pathways that result in an appropriate response to

Cells have stress sensors that are highly specialized for survival in a particular environment. The specific mechanism of how TM cells sense various stimuli is largely unknown [48]. Mechanosensitive ion channels, specifically calcium-dependent maxi-K+ channels, are present in TM cells [113]. Stretch-activated channels located on the TM cell membrane are predicted to increase intracellular calcium levels. Another potential mechanism through which TM cells sense mechanical stress is the ECM. ECM receptors such as integrins are connected to the cytoskeleton, which is attached to the nuclear membrane. Thus, signals may be propagated from the extracellular environment where the mechanical stress occurs to the nucleus where gene expression can be altered in response to the stress [114]. Although the consequences of oxidative stress-related damages have been extensively studied, how the cell initially senses oxidative stress remains largely unknown [48,115]. In fact, the identification of oxidative stress sensors in any cell type has proven to be very difficult. In the future, identifying more sensors in TM cells will give insight into how TM cells achieve specificity in responding to specific stresses such as mechanical and oxidative stresses.
