Pro-Inflammatory Cytokine Regulation by HIF-1α in Glaucoma
In glaucoma, neurons are dying slowly and leading to blindness. Numerous detrimental factors, including low oxygen (hypoxia), play key roles in the progression of this disease. Our team has shown that the neurotoxic proteins, including cytokines and hypoxia-inducible transcription factor-1 alpha (HIF-1 alpha) are up-regulated and facilitate neuronal death in glaucoma. The studies in this project seek to limit the up-regulation of such neurotoxic proteins to slow/halt neuronal death in glaucoma.
This project will determine if blocking HIF-1α-stabilization provides retina neuroprotection via suppression of pro-inflammatory cytokines.
In Specific Aim #1, the studies will determine what changes in RGC function and integrity occur when HIF-1alpha activity is manipulated, using an in vivo model. Studies will also determine that how RGCs die during the progression of glaucoma, and if there is involvement of caspases in RGC death. In Specific Aim #2, the studies will determine if HIF-1α blockage by selective HIF-1α inhibitors blocks the production of pro-inflammatory cytokines and provides neuroprotection. The idea that RGC neuroprotection may result from blocking HIF-1α stabilization and subsequently blocking its downstream targets (e.g., pro-inflammatory cytokines) during the early stages of glaucoma is highly innovative and it has not been tested. The outcome of this study will pave the way to identify new therapeutic agents for glaucoma therapy. A comprehensive understanding of HIF-1α and its associated genes will be critical to develop HIF-1α inhibitors for clinical trials. The successful completion of these studies will be translational, as it will directly apply to glaucoma therapy.