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

Project: A - Government Institutionb - National Science and Technology Council

Project Details

Description


Dysregulatory neuroinflammation is the crucial pathological factor of glaucoma, and involved retinal ganglion injury, Muller dysfunction and microglia activation. Neuroinflammation is the crucial factor to enhance the death of retinal ganglion cells (RGC) and axonopathies. Much evidence has been indicated reduction of inflammatory mediators, cytokines, and matrix metalloproteinase (MMPs) which could improve in the RGC death and axonopathies in glaucomatous progression. Current findings suggested that regulation of ary hydrocarbon receptor (AHR) could affect neuroinflammatory responses and glial activation through NF-B and Akt signal effects. In the third year studies, we had clarified AHR activation with attenuation of two retinal Muller cells and microglial activation, also the signal effects. Especially, the studies of TNF- on MMP-9 activation and expression in human retina Muller cells (MIO-M1). The effects of AhR agonists were evaluated on ERG, neuroinflammatory events and necroptosis in acute ocular hypertension. Furthermore, the gene defect mice AHR
(+/-) were used studied on their retinal function and conditions. The results were clarified TNF- and S100B with stimulatory effect of human retina Muller cells (MIO-M1),
and AhR agonist FICZ could inhibit TNF--induced MMP-9 gelatinolysis and its protein trafficking. FICZ exerted diverse effects on the induction of expression of CYP1B1
and COX-2, but reduction of AhR proteins in retina Muller cells. It also attenuated the production of MCP-1 induced by S100B and TNF- induction. FICZ had inhibitory effects on
the signal AKT and NFB in retina Muller cells and microglia. However, FICZ exerted little effcts on thde oxidative injury of retinal Muller and R28 cells. AhR
agonist BNF had the protective effects on ERG/PhNR and MMP9 activation in acute glaucoma. It was found AHR (+/-) mice exerted more deterioration of ERG/PhNR and MMP-9
activation. The summary of this three-years research, we investigated and elucidated the important effects and mechanisms of AHR on activated human Muller cells and
microglia. Especially, AhR agonist abrogated MMP-9 activation through regulation of release and degradation of MMP-9. Also, the inhibitory effect of FICZ on Akt signaling was clarified. Through these glaucomatous studies of AHR agonist manipulation and AHR (+/-) mice, it implies AhR with protective effects on retinal functions in glaucoma.
StatusFinished
Effective start/end date8/1/227/31/23

Keywords

  • glaucoma
  • Aryl hydrocarbon receptor
  • optic nerve axon
  • retinal ganglian cells
  • Muller cells
  • microglia
  • neuroinflammation
  • necroptosis
  • AHR agonist
  • rAAV
  • vitrectomic washing-soring cells

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