Xeroderma Pigmentosum A Deficiency Results in Increased Generation of Microvesicle Particles in Response to Ultraviolet B Radiation
Jeffrey B. Travers, M.D., Ph.D. (Advisor); Michael G. Kemp, Ph.D. (Committee Member); Ji Chen Bihl, M.D., Ph.D. (Committee Member)
Master of Science (MS)
Xeroderma Pigmentosum is a genetic disorder in which ability to repair DNA damage such as from UV radiation is decreased. Nucleotide excision repair is known for repairing DNA damage caused by UV radiation and XPA plays a major role in recognizing and eliminating abnormal section of DNA. Therefore, XPA deficiency decreases repair efficiency of DNA. Of note, XPA deficiency is linked with photosensitivity. Microvesicle particles are membrane-bound particles which are released into the extracellular environment in response to multiple stimuli including the lipid Platelet activating factor (PAF). Previous studies have shown that XPA deficiency can induce increase production of reactive oxygen species and generates large amounts of PAF agonists produced non-enzymatically. Hence, the present studies are designed to study if XPA deficiency induces higher UVB-MVP release via PAF-R signaling pathway. Studies involving a XPA- deficient keratinocyte cell-line were able to show that UVB irradiation can cause increase MVP release. Similarly, XPA knockout (KO) mice generated increased MVP with UVB irradiation both in skin as well as plasma in comparison to wild-type mice. Increased production of cytokines (TNF-alpha and IL-6) were also seen in XPA KO mice. However, absence of XPA did not affect MVP release when treated with PAF-R agonist or phorbol ester TPA. Topical application of the acid sphingomyelinase (aSMase) inhibitor imipramine was able to inhibit UVB induced MVP release and pro-inflammatory cytokines. Likewise, genetically knocking down aSMase affected MVP release by UVB irradiation in comparison to wild-type and XPA KO mice. As MVP been involved in UVB signaling, inhibiting MVP release by pharmacological means might be a novel therapeutic approach in photosensitive conditions.
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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