Our hypothesis is that cellular senescence in the aqueous humor outflow pathway is involved in the pathogenesis of the increase in outflow resistance that occurs in many types of glaucoma. More specifically, we hypothesize that the different kinds of chronic stress over time affecting the cells of the outflow pathway and, in particular, oxidative stress, lead to the progressive accumulation of misfolded proteins which overwhelm the degradative capacity of the proteasome in outflow pathway cells; that this results in chronic activation of the ER stress response which, in turn, activates the MKK3/MKK6/p38MAPK/TGFbeta pathway and triggers a stress-induced senescent phenotype in the trabecular meshwork (TM) cells; and that the gradual accumulation of cells with such a proteasome-impaired/senescent phenotype contributes to the pathological changes that lead to increased outflow resistance in the TM. This hypothesis is supported by our preliminary data showing that: 1) chronic oxidative and mechanical stress can induce proteasome failure and a senescent phenotype in TM cells; 2) direct chronic inhibition of the proteasome can lead to a similar senescent phenotype; 3) there is an increase in senescent cells with age in normal TM and; 4) the TM from POAG donors has a significantly higher number of senescent-associated -beta-galactosidase cells than those from age-matched controls. To test our hypothesis, we propose the following three specific aims: SA-1) Evaluate whether chronic proteasome inhibition alone induces cell senescence through activation of the same regulatory pathway as chronic oxidative stress; SA-2) Evaluate whether induction of cell senescence results in pathophysiological changes that lead to increased outflow resistance; and SA-3) Evaluate whether activation of proteasome function can delay the induction of cellular senescence and pathological changes in the TM after chronic oxidative stress. We believe that these studies will provide important insights into possible pathophysiological mechanisms involved in glaucoma. ? ? ?
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