Date of Award

January 2025

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Mathieu F. Bakhoum

Abstract

Pterygium is a fibrovascular growth that can cause significant discomfort and vision loss. Ultraviolet (UV) exposure is a leading environmental risk factor. We hypothesized that UV triggers the de-repression of transposable elements (TEs), including endogenous retroviruses (ERVs), and subsequently activate double-stranded RNA and DNA sensors such as RIG-I and cGAS. Additionally, we sought to characterize the composition and activities of key cellular subtypes in pterygium. In the present study, we used Telescope to analyze publicly available RNA sequencing data from pterygia and healthy conjunctiva specimens for TE expression. We then repeated this analysis using RNA collected from cultured human conjunctival fibroblasts exposed over multiple days to a range of UV intensities. We also conducted proliferation and wound-scratch assays with these cell lines. Lastly, we performed single-nucleus RNA sequencing on snap-frozen pterygium and conjunctiva specimens. We found that pathways involved in cellular stress, nucleic acid sensing, and innate immune signaling were upregulated in both cell lines exposed to increased amounts of UV energy as well as pterygia; we also observed differential expression of TEs. Our single-nucleus RNA sequencing study of human pterygium specimens identified changes in epithelial cell composition consistent with a field effect phenomenon signaling, and highlighted ligand-receptor interactions associated with macrophage activation. Taken together, our findings suggest a mechanistic link between environmental factors and pterygium pathogenesis. Understanding the molecular pathways activated by UV exposure may aid in developing therapeutic strategies.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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