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Pranali S. Manjrekar-Thesis.pdf (1.33 MB)

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Xeroderma Pigmentosum Type A Deficiency Results in Increased Generation of Microvesicle Particles in Response to Ultraviolet B Radiation and Solar Simulated Light via Platelet-activating Factor Receptor Signaling Pathway

Manjrekar, Pranali Sushil
http://orcid.org/0009-0001-3426-8449
http://rave.ohiolink.edu/etdc/view?acc_num=wright1683900908337128

Abstract Details

2023, Master of Science (MS), Wright State University, Pharmacology and Toxicology.
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.
Jeffrey B. Travers, M.D., Ph.D. (Advisor)
Ravi P. Sahu, Ph.D. (Committee Member)
Yanfang Chen, M.D., Ph.D. (Committee Member)
67 p.
Pharmacology; Toxicology
Xeroderma Pigmentosum; Ultraviolet B Radiation; UVB; microvesicle particles; Solar Simulated Light; Platelet-activating Factor; acid sphingomyelinase; XPA deficiency; photosensitivity

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Citations

  • Manjrekar, P. S. (2023). Xeroderma Pigmentosum Type A Deficiency Results in Increased Generation of Microvesicle Particles in Response to Ultraviolet B Radiation and Solar Simulated Light via Platelet-activating Factor Receptor Signaling Pathway [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1683900908337128

    APA Style (7th edition)

  • Manjrekar, Pranali. Xeroderma Pigmentosum Type A Deficiency Results in Increased Generation of Microvesicle Particles in Response to Ultraviolet B Radiation and Solar Simulated Light via Platelet-activating Factor Receptor Signaling Pathway. 2023. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1683900908337128.

    MLA Style (8th edition)

  • Manjrekar, Pranali. "Xeroderma Pigmentosum Type A Deficiency Results in Increased Generation of Microvesicle Particles in Response to Ultraviolet B Radiation and Solar Simulated Light via Platelet-activating Factor Receptor Signaling Pathway." Master's thesis, Wright State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=wright1683900908337128

    Chicago Manual of Style (17th edition)

wright1683900908337128
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This open access ETD is published by Wright State University and OhioLINK.