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NIH grant 1R01EY037652-01: The Impact of Hypoxia on Mustard Vesicant-Induced Eye Injury
Institute: {'code': 'EY', 'abbreviation': 'NEI', 'name': 'National Eye Institute', 'admin_org_id': '12500073', 'admin_funding_url': ''}. PI: Jia Yin. Award: $1496120.
Start: 2026-09-30T00:00:00.
Project Summary
Mustard vesicants, such as sulfur mustard and nitrogen mustard, are chemical weapons of mass destruction
that can severely damage the eye. Acute exposure leads to corneal epithelial defects, corneal edema,
conjunctival injection, eyelid swelling, and intraocular inflammation. Chronic disease is characterized by limbal
ischemia, conjunctival vascular abnormalities, corneal scarring and neovascularization, and damage to the iris
and retina. Despite numerous studies in humans and animals, the underlying mechanisms of mustard vesicant-
induced eye injury remain unclear, and to date, there is no targeted treatment. Hypoxia (low oxygen levels) plays
critical roles in mustard vesicant-induced skin and lung injuries and in non-vesicant ocular chemical burns, but
its role in ocular mustard vesicant injury remains unknown. Hypoxia-inducible factors (HIFs) are master
transcription factors that mediate cellular adaptation to hypoxia. We hypothesize that mustard vesicant exposure
to the eye induces immediate and persistent hypoxia and HIF signaling, which promote cellular damage and
lead to excessive inflammation and pathological angiogenesis. We will test this hypothesis using human tissues
and animal models and employ a variety of cellular and molecular methods in three specific aims. In Aim 1, we
will determine intraocular oxygen levels and HIF activation after mustard exposure in vivo. We will determine HIF
downstream signaling using human ocular tissues in vitro. In Aim 2, we will assess whether HIF activation
following mustard exposure induces mitochondrial dysfunction, metabolic reprogramming, and oxidative stress
in ocular tissues. We will modulate HIF activation with promoters and inhibitors, and assess their effects on
glycolysis, mitochondrial function, and the production of reactive oxygen species in ocular cells and tissues. In
Aim 3, we will treat mustard vesicant-exposed animals with topical oxygen therapy or HIF inhibitors. We will
determine whether these therapies can mitigate eye injury by reducing excessive inflammation and pathological
angiogenesis. We believe that hypoxia and HIF activation are not only acute responses to mustard injury but
also initiate and propagate other pathophysiological processes, which in turn exacerbate and perpetuate tissue
hypoxia beyond the acute stage, creating a vicious cycle of hypoxia and cellular/tissue damage. Successful
completion of this proposal will not only fill knowledge gaps in chemical injury-related hypoxia research but also
provide the first proof-of-concept data demonstrating the therapeutic potential of reversing tissue hypoxia or
suppressing HIF signaling as novel topical medical countermeasures for mustard vesicant exposure.document fetched 2026-10-24 02:46