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The Impact of Hypoxia on Mustard Vesicant-Induced Eye Injury

Award Number: R01EY037652
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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The Impact of Hypoxia on Mustard Vesicant-Induced Eye Injury - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,496,120 )
2026	2026	TUFTS MEDICAL CENTER PARENT, INC.	800 WASHINGTON ST	BOSTON	MA	02111	SUFFOLK	USA	Vision Research	000	1	9/17/2026	NEW	$1,496,120
														Subtotal = $1,496,120

Grand Total All Awards = $1,496,120

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The Impact of Hypoxia on Mustard Vesicant-Induced Eye Injury

Award Number: R01EY037652

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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