Friday, May 9, 2025
5/9/2025
Investigating the role of cGMP signaling in glaucomatous neurodegeneration - PROJECT SUMMARY Glaucoma is the world’s leading cause of irreversible blindness, which evolves from degeneration of retinal ganglion cells (RGCs) and their axons which form the optic nerve. Glaucoma is characterized by sensitivity to intraocular pressure (IOP), with susceptibility increasing with age. Current treatments lower IOP to relieve stress to RGC axons, but many patients continue to lose vision. Thus, an unmet clinical need is a treatment that addresses RGC degeneration directly. Our long-term goal is to probe the mechanisms of RGC degeneration in glaucoma to identify novel therapeutic targets to protect and potentially restore vision. The objective of this proposal is to investigate the potential role of the cyclic nucleotide guanosine monophosphate (cGMP) in countering RGC degeneration in glaucoma. Glaucoma involves complex pathogenic processes in the retina and optic nerve. These include interactions between RGCs, astrocyte glia, and microvascular elements, which is our focus here. cGMP is a vasoactive second messenger produced by the nitric oxide (NO)-sensitive enzyme soluble guanylate cyclase (sGC, referred to in this proposal as GC1), which relaxes vascular smooth muscle tissue to increase blood flow. Longstanding evidence suggests that cGMP signaling is impaired in glaucoma. Patients show decreased ocular cGMP, while polymorphisms in genes encoding GC1 lead to increased incidence of glaucoma with early paracentral visual field loss. Our published work demonstrates that aberrant cGMP signaling induced by global knockout of GC1 (GC1-/-) leads to gross morphological abnormalities in retinal astrocyte and vascular networks that precede age-related RGC degeneration. Finally, increasing cGMP with a PDE-5 inhibitor (tadalafil) protects RGCs in multiple murine models of glaucoma. Based on these findings, this proposal will test the central hypothesis that disrupted cGMP signaling in glaucoma degrades astrocyte-vascular networks, leading to RGC metabolic stress and subsequent axon degeneration. As a corollary, we will test whether increasing cGMP signaling specifically in either astrocytes or RGCs slows progression. This hypothesis is supported by preliminary data that show aging GC1-/- mice exhibit (1) reduced retinal glucose uptake coincident with decreased glucose transporter-1 (GLUT1) and mitochondrial proteins and (2) increased RGC oxidative stress and RGC degeneration. Here we will discern age vs. IOP-dependent effects of cGMP signaling by combining cell-specific transgenics and viral-targeted gene disruption with imaging, electrophysiology, and visual function testing in our microbead occlusion model in mice. In Aims 1 and 2 we investigate how cGMP signaling alters astrocyte and vascular cellular connectivity, and RGC mitochondrial function and oxidative stress. In doing so, these experiments will reveal novel cell-specific roles of cGMP in the retina that may be targeted therapeutically to preserve vision in glaucoma by abating RGC degeneration, possibly by boosting mitochondrial function and reducing metabolic stress – in Aim 3 we test this possibility.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).