Wake Forest University Health Sciences

The Mechanism of Vesicant-induced Ocular Injury - the Eye Is 10 Times More Susceptible to Exposure to Vesicants Than Other Organs. the Aftermath of These Exposures and Their Impacts on Human Vision Are Easy to Underestimate Since Many Ocular Symptoms May Manifest Long After Exposure. Thus, It Has Been Documented That the Survivors of a Vesicant Attack During the Iraq–iran War Not Only Experienced Corneal Damage in the First 30 H After the Attack But Also Manifested Diminished Scotopic and Photopic Electroretinogram Responses 40 Years Later. in Addition, Delayed Symptoms in These Individuals Also Included Central Retinal Vein Occlusion and an Increase of Soluble Vegf-a in Their Tears. Currently, There Is No Effective Antidote to Combat Vesicant-induced Ocular Damage and Vision Loss in Humans. Therefore, Our Long-term Goal Is to Generate Effective Medical Countermeasures to Mitigate the Consequences of Such Exposures. This Goal Will Not Be Achievable Unless We Increase Our Molecular Understanding of the Underlying Mechanism Responsible for the Ocular Damage and Progressive Ocular Injuries Caused by Vesicant Exposure. Therefore, in This Proposal, We Analyze Direct Ocular Exposure (DOE) to Vesicants to Identify the Molecular Signaling Driving the Acute and Chronic Stages of Corneal, Vascular, and Retinal Pathobiology. Focusing on the Unfolded Protein Response (UPR)-TRIB3 Downstream Signaling, We Hypothesize That, Upon Doe, Not Only the Corneal Tissue But Also Other Ocular Tissues, Such as Vascular and Retinal Tissues, Are Damaged, and Depending on the Severity, Vesicant Exposure Activates UPR-TRIB3 Signaling in the Cornea, Which Further Propagates the Vegf Signal, Causing Blood Vessel Dysfunction and Retinal Injury. to Dissect the Mechanistic Link Between Direct Ocular Exposure and Pathophysiology, We Propose a Diverse Spectrum of Step-by-step Strategies and a Broad Arsenal of Tools. These Tools Include Different Animal Models (mice and Tree Shrews), Corneal and Retinal Ex Vivo Tissue, Corneal and Retinal Cultured Cells, Two Different Toxicants (lewisite and Nitrogen Mustard), and Genetic Ablation of TRIB3 in the Corneal, Vascular, and Retinal Tissue to Block the TRIB3-VEGF Signal and Delay the Onset of Ocular Injuries. the Latter Will Be Confirmed in Experiments With Vesicant-exposed Animals Treated With a Small-molecule Inhibitor Vegf-trap-eye. Therefore, in Aim #1, We Propose to Investigate Whether Doe to Vesicants Activates the UPR-TRIB3-VEGF Axis, Acting as a Molecular Driver of Corneal Tissue Injury. We Will Demonstrate the Molecular Consequences of Corneal-originated TRIB3-VEGF Axis Activation. in Aim #2, We Intend to Determine Whether Secreted Corneal TRIB3-MEDIATED Vegf Signal Drives Vascular Pathogenesis by Assessing Corneal Neovascularization (NV) and Retinal Blood Vessel Disruption. in Aim #3, We Plan to Investigate Whether Secreted Cornea- and Vascular-mediated Vegf Drives the Pathophysiology of Retinal Injury Through the Activation of UPR-TRIB3. These Studies Will Identify a Novel and Highly Interesting Molecular Mechanism by Which the Activated UPR-TRIB3-VEGF Axis Acts as a Molecular Driver of Ocular Tissue Pathobiology and Will Establish a Groundwork for Future Mechanistic Studies of Ocular Toxicity in Exposed Populations.