The Retinoprotective Role of Aryl Hydrocarbon Receptor Activation in Glaucomatous Progression( I )

Glaucoma is a complicated, multifactorial disease involved retinal ganglion injury, microglia activation, and neuroinflammation have been involved with the death of retinal ganglion cells and axon degeneration. Ary hydrocarbon receptor (AHR) has been found not only the key nuclear regulator of xenobiotics, but works as an important modulator on cytoplasmic signaling among the inflammatory cascades. Much evidence has been indicated microglia/monocyte activation, Muller cell dysfunction, overproduction of inflammatory mediators/cytokines and matrix metalloproteinase (MMPs) which participate in the disruption of blood-retina barrier and specific neuron death during glaucomatous progression. Microglia/monocyte activation is evident with specific stress, and the immune response elicited the induction of several proinflammatory mediators, including tumor necrosis factor-a, HMGB1 and matrix metalloproteinase (MMP). These pathological progression could cause retinal necroptosis into cellular death and inflammation. Key regulators of neuroinflammation are the signaling Signal Transducer and Activator of Transcription (STAT), NF-κB and MAPK. Also, AHR could be association with STAT by specific functionally association, which results in downregulation of neuroinflammation. Current findings suggested that AHR agonists could affect neuroinflammatory responses and glial activation. However, there were opposite findings in some pathological retinal conditions in vivo. Therefore, knowledge remains limited on the contributions of AHR regulators to the treatment of glaucoma. In our preliminary studies, it was found a AHR agonist with inhibition on Muller MMP-9 gelationolysis and microglial iNOS protein expression. Also, this specific agonist improved retina ERG deficit in glaucomatous animal model. The aims of this project will to investigate three major points, first, to evaluate and identify the effects of AHR in glaucoma, including the functional studies (ERG/PLR), expression of inflammatory mediators in glial microglia/Muller cells and necroptosis. Also, the regulatory functions were compared as cell-specific actions. Second, to identify the mechanisms of these regulators on the signallings of AHR by their interference with phosphorylation or protein-protein binding interactions. Also the upstream signal effectors such as STAT, p56 and Akt will be clarified. Third, we will execute the AHR KO mice and rAAV-AHR delivery to prove the retinal protective functions and mechanisms of AHR regulation in glaucomatous injury and interaction with microglia and Muller cells. On the other hand, the AHR profiles of human vitrectomy-sorting retinal cells will be studied to understand and compare the AHR therapeutic issues in glaucoma. Our study will elucidate the important mechanisms of targeting AHR as promising therapeutic target to counteract the progression of glaucoma.