Friday, May 9, 2025
5/9/2025
Unraveling the corneal and retinal mechanisms of chemical injury - Abstract: Chemical threat agents can potentially be weaponized to cause mass casualties and such egregious events are of grave concern to homeland security. Sulfur mustard and its analog nitrogen mustard (NM) are vesicants that cause severe acute injury to ocular tissues and ultimately develop fibrotic scarring leading to vision loss. As medical treatments for vesicant injury have yet to be developed for paucity of a complete understanding of their pathophysiological mechanisms, this unmet medical need remains an urgent matter of importance to the Chemical Countermeasures Research Program (CCRP). Under an exploratory R21 grant funded by the CCRP, we have discovered that NM injury to the mouse cornea triggers a rapid and profound induction of retinal gliosis. This retinal response is coordinated in reactive Muller glia with activation of the posttranslational modification (PTM) known as citrullination. This finding extends our prior results showing that retinal hypercitrullination driven by the enzyme peptidyl arginine deiminase (PAD)-4 is a shared pathological feature that is common to a number of different injury and disease paradigms. But critical gaps remain regarding the molecular steps involved in the PAD-hypercitrullination axis. As other published reports have shown that NM crosslinks tumor suppressor p53 and the p53 DNA damage pathway interacts with PAD4, these data provokes an interesting idea whether these two major orchestrators of pathological response are tied to activating hypercitrullination in both the cornea and retina. In this R01 grant proposal, we will investigate the acute and chronic (delayed) injury mechanisms of NM across the cornea and retina in mouse and rat models. Specifically in Aim 1, we will investigate the molecular mechanisms of the p53-PAD axis involving corneal hypercitrullination and identify the relevant PAD using both in vivo and cell culture models to study NM injury. In Aim 2, we will characterize the corneal and retinal citrullinomes of NM injury using proteomics by examining the temporal changes over the early and chronic stages. This study will allow us to identify key PAD substrates of acute and chronic injury states, permitting us to decipher the evolution of key protein players modified by citrullination in perpetuating corneal and retinal pathology. We believe this in-depth investigation into hypercitrullination in the NM injured eye could unravel novel mechanisms and druggable PAD targets that would be critical for drug discovery to combat chemical injury to the human eye. Given that PADs are already being investigated as targets for several common diseases, the likelihood of clinical drugs becoming available for humans in the near future makes this an attractive target class for further mechanistic assessment.
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).