AIBP-mediated neuroprotection in glaucomatous optic neuropathy

Glaucoma is a leading cause of blindness worldwide and glia-driven neuroinflammation is a key element in the pathogenesis of glaucoma. Increasing evidence from clinical studies indicate that primary open-angle glaucoma is linked to single-nucleotide polymorphisms of toll-like receptor 4 (TLR4 ), mitochondrial cytochrome c oxidase(COX) subunit I of the oxidative phosphorylation (OXPHOS) complex (Cx)-IV, ATP-binding cassette transporter A 1 (ABCA 1), as well as Cholesterol-24S-hydroxylase (CYP46A 1 ), suggesting that TLR4-mediated neuroinflammation, cholesterol efflux and/or OXPHOS stress-mediated mitochondrial dysfunction play roles in glaucoma pathogenesis. The goal of current study is to test the novel concept that Al BP-mediated inhibition of TLR4 activation is one of the endogenous protective mechanisms to inhibit mitochondrial dysfunction and excessive glia-driven neuroinflammation in glaucoma. The Specific Aims of th is proposal are: (1) to determine the protective effect of AIBP amplification on mitochondrial dynamics and bioenergetics, as well as dendritic and synaptic remodeling in glaucomatous RGCs; (2) to identify the mechanisms responsible for the protective effects of AIBP against glaucomatous glia-driven neuroinflammation and RGC degeneration; and (3) to evaluate the therapeutic potential of AIBP overexpression on the structural integrity and synapses linking RGCs and the central visual pathway. Dr. Wonkyu Ju (Principal Investigator) in the Viterbi Family Department of Ophthalmology at Shiley Eye Institute in University of California San Diego will oversee all aspects of the study including protocol development, quality control, data collection, statistical analysis, result interpretation and manuscript preparation. Dr. Wenbo Zhang (Consortium Principal Investigator) in the Department of Ophthalmology at University of Texas Medical Branch at Galveston will be responsible for providing his intellectual knowledge to work closely with Dr. Ju in experimental design and data collection and analysis from the eyes of microbead induced experimental glaucoma. Moreover, his lab will conduct experiments for AIBP overexpression and recombinant AIBP protein treatment in the microbead model with some molecular biological experiments (Western blots) and vision function tests such as pSTR and PERG.