Deciphering glaucoma neurovascular dysfunction: identifying and validating endothelial mediators with ligandomics

The National Eye Institute awarded Baylor College of Medicine $100,228 on March 22, 2027, under the Vision Research program (CFDA 93.867) to validate endothelial mediators in glaucoma neurovascular dysfunction using ligandomics technology.

The recipient will independently validate the binding selectivity of glaucoma-associated endothelial ligands to ocular hypertensive versus healthy retinal vessels and verify their functional roles in retinal ganglion cell loss and neurovascular dysfunction in glaucoma models. Work proceeds in two aims: global mapping and independent validation of glaucoma-selective endothelial ligands for retinal and optic nerve head vessels, followed by characterization of the functional role and therapeutic potential of ocular hypertensive-selective endothelial ligands to modulate glaucoma pathogenesis in mice. The project centers on the hypothesis that glaucoma-selective endothelial ligands modulate retinal ganglion cell function through neurovascular coupling, extending beyond current therapies that target intraocular pressure alone.

Performance occurs in Houston, Texas, with an ultimate completion date of July 23, 2029. The assistance type is a Project Grant.

Abstract

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by progressive loss of retinal ganglion cells (rgcs) and optic nerve head (ONH) degeneration. Elevated intraocular pressure (IOP) or ocular hypertension (OHT) is widely recognized as the primary risk factor and the sole target of currently approved therapies. However, despite efforts to lower IOP, disease progression persists in many patients, leading to the proposal of the vascular theory of glaucoma. In this theory, vascular abnormalities and neurovascular unit (NVU) dysfunction, alongside elevated IOP, contribute to glaucoma onset and progression. Despite evidence supporting the involvement of both mechanical and vascular factors in experimental animals and clinical patients, neurovascular interplay and related molecular mechanisms in glaucoma remain elusive. To tackle this challenge, we applied an innovative technology of ligandomics to retinal vessels of OHT and healthy mice and globally mapped nearly 200 glaucoma-associated endothelial ligands. The objective of this project is to independently validate the binding selectivity of identified EC ligands to OHT VS. Healthy retinal vessels and verify their functional roles in mitigating or exacerbating RGC loss and neurovascular dysfunction in glaucoma mice. The central hypothesis is that glaucoma-selective endothelial ligands are capable of modulating RGC function through neurovascular coupling. In aim 1, i will globally map glaucoma-selective endothelial ligands for retinal and ONH vessels for overlapping analysis and independently validate their binding selectivity to OHT VS. Healthy vessels. In aim 2, i will characterize the functional role and therapeutic potential of OHT-selective endothelial ligands to modulate glaucoma pathogenesis in OHT mice. Successful implementation of the proposed studies will provide an in-depth understanding of NVU dysfunction in glaucoma pathogenesis, delineate unknown neurovascular signaling pathways, and identify novel therapeutic targets. This project will elucidate the molecular mechanisms of the century-old vascular theory of glaucoma and has the potential to develop a novel strategy of neurovascular therapy for glaucoma.