Publication Date
2023
Document Type
Thesis
Committee Members
Jeffrey B. Travers, M.D., Ph.D. (Advisor); Ravi P. Sahu, Ph.D. (Committee Member); Yanfang Chen, M.D., Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Increased vulnerability to the DNA-damaging effects of ultraviolet (UV) radiation is a hallmark of the uncommon genetic disorder Xeroderma Pigmentosum (XP). The Nucleotide Excision Repair (NER) route uses the DNA Damage Recognition and Repair component XPA to identify and get rid of damaged DNA segments. Although the solar UVB (290-320 nm) radiation is necessary for humans to produce vitamin D, it may also induce erythema and inflammatory reactions, and in some pathological situations, such as XPA deficiency, results in increased UV responses (photosensitivity). Our group has previously shown, using cell lines and mice, that increased synthesis of the lipid mediator Platelet-activating factor (PAF) is what causes UVB-induced amplified effects linked to XPA deficiency. Importantly, our team has recently found that PAF-receptor (PAFR) signaling induces the activation of the enzyme acid sphingomyelinase (aSMase), resulting in the release of tiny subcellular membrane-bound particles known as microvesicle particles (MVPs) from the plasma membrane of keratinocytes. The objective of the ongoing research is to ascertain whether XPA deficiency stimulates increased MVP synthesis in response to UVB and more clinically significant solar-stimulated light (SSL; includes all UV associated with sunlight) via the PAFR signaling pathway and whether inhibiting PAFR or aSMase can significantly decrease photosensitivity. Studies using a keratinocyte cell line deficient in XPA showed more MVP release when exposed to UVB and SSL radiation than XPA-positive cells. UVB and SSL treatment of XPA KO mice resulted in increased MVP release, exaggerated erythema, and cytokine production in comparison to wild-type mice. It was discovered through genetic methods utilizing mice lacking in PAFRs and aSMase that these heightened UV responses depended on a new route involving PAFR-mediated aSMase activation. Finally, experiments on mice showed that administration with the aSMase inhibitor imipramine prevented UV-induced photosensitivity. This research pinpoints a model MVP route that is responsible for the aberrant UV responses linked to XPA deficiency. These investigations also provide novel treatment targets for photosensitivity.
Page Count
67
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2023
Copyright
Copyright 2023, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0009-0001-3426-8449
