The role of vascular ligands and neurovascular dysfunction in glaucoma and therapeutic potential

Project Summary Elevated intraocular pressure (IOP) is the only modifiable risk factor of glaucoma, and all approved drugs for glaucoma aim to lower IOP but with limited efficacy to prevent retinal ganglion cell (RGC) loss. Mounting evidence suggests that both ocular hypertension (OHT) and vascular abnormalities coordinately contribute to the pathogenesis, whereas molecular mechanisms remain elusive. In the neurovascular unit (NVU), endothelial cells (ECs) and RGCs don’t have direct physical contact but are part of a complex interaction network connected via pericytes and glial cells. The daunting challenge to confirm the role of NVU dysfunction in glaucoma pathogenesis is the lack of EC-specific ligands with minimal binding to RGCs to demonstrate modulation of RGC function and survival through the NVU. To address the challenge, we recently developed an innovative technology of ligandomics to globally map cell-binding ligands with simultaneous binding activity quantification. This technology has led to the discovery of disease-restricted angiogenic factors and development of first-in- class disease-targeted anti-angiogenic therapies by our group. The objective of this project is to unequivocally confirm the contribution of the NVU to glaucoma pathogenesis and identify EC ligands with potential for neuroprotective therapy. Our central hypothesis is that OHT-restricted EC-specific ligands with undetectable binding to RGCs can mitigate or exacerbate RGC dysfunction and loss indirectly via the NVU in glaucoma. In Aim 1, we will globally map all ligands binding to OHT and healthy retinal ECs, RGCs, pericytes and glial cells with simultaneous binding activity quantification by ligandomics. Quantitative comparison of entire ligandomes will systematically identify OHT-selective EC-specific ligands with minimal binding to RGCs and glial cells. In Aim 2, OHT-selective EC-specific ligands will be independently validated their binding to NVU cells to confirm their disease binding selectivity and cell-binding specificity. In Aim 3, OHT-selective EC-specific ligands will be functionally validated for their capacity to mitigate or exacerbate RGC dysfunction and loss in glaucoma eyes. Validated EC-specific ligands capable of modulating RGC function and survival are promising targets to develop novel neuroprotective therapy with minimal side effects on healthy NVU cells. To our knowledge, ligandomics is the only omics technology to systematically identify disease-selective cell-specific ligands and is broadly applicable to all types of cells and neurological diseases with potential for transformative impact on neuroscience research and neuroprotective therapy.