Friday, July 26, 2024
7/26/2024
Pterygium is a raised wedge-shaped fibrovascular growth of the conjunctiva that migrates into the transparent cornea. Pterygium causes significant discomfort and can lead to a decline in vision through induction of irregular astigmatism and obstruction of visual axis. The exact molecular mechanism leading to pterygium formation and progression is unknown. Consequently, there are no available medical therapies available for pterygium prevention or treatment. Inflammation biomarkers are upregulated in pterygium, and ultraviolet (UV) exposure is the most significant risk factor for pterygium formation. However, the mechanism by which UV exposure leads to inflammation, and whether an inflammatory response plays a causative role in pterygium progression is unknown. Our preliminary data based on analysis of human pterygium samples and normal conjunctiva demonstrate evidence of activation of non-canonical NF-κB signaling in human pterygia that is coupled with de-repression of endogenous retroviruses (ERVs). ERVs are viral retroelements that have integrated into the human genome, and their transcriptional de-repression has been associated with increased cellular inflammation through the production of double-stranded RNA (dsRNA) and DNA (dsDNA), leading to the activation of the dsRNA and dsDNA sensors, RIG-I/MDA5/MAVS and the cGAS-STING innate immune pathways, respectively. Aberrant and dysregulated activation of cell-intrinsic, innate immune pathways has been implicated in cellular migration and proliferation through activation of non-canonical NF-κB signaling. In this proposal, we will test the central hypothesis that chronic UVB exposure induces transcriptional de- repression of ERVs in conjunctival cells leading to increased cellular proliferation and migration through activation of the cGAS–STING pathway and downstream non-canonical NF-κB signaling. This hypothesis will be tested using two independent aims. Under Aim 1, we will test the epistatic dependency of the migratory phenotype of pterygium-derived cells on non-canonical NF-κB signaling, which has been implicated in mediating a migratory and invasive phenotype in cancer models. We will establish pterygium-derived cells obtained from surgical specimens at our clinical practice. Under Aim 2, we will determine whether chronic UVB exposure leads to upregulation of non-canonical NF-κB signaling, and test whether activation of non-canonical NF-κB signaling is mediated by de-repression of ERVs and downstream cGAS-STING activation. By utilizing genetic and pharmacologic manipulation of key components of the cGAS-STING and non-canonical NF-κB signaling pathways, we seek to establish a mechanistic link between UVB exposure and a migratory phenotype. The overarching goal of this proposal is to elucidate the molecular mechanisms underlying pterygium formation and progression, and identify molecular targets that are amenable to pharmacologic intervention. The Principal Investigator is an Assistant Professor at Yale University and runs an independent laboratory. Our team has the clinical expertise and the resources to complete the proposed experiments.
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).
