Thursday, November 21, 2024
11/21/2024
Abstract Humans are subjected daily to multiple and often simultaneous environmental stressors, yet the complex interaction of these agents remains an understudied area. Of significance, the exposure to environmental ultraviolet radiation (UVR) has profound effects on the skin and induces systemic consequences from vitamin D production to immunosuppression to melanoma and non-melanoma skin cancers. Besides, ubiquitous environmental pollutants, polycyclic aromatic hydrocarbons (PAH) exert immunomodulatory as well as pro- carcinogenic effects. However, there is a significant knowledge gap of interactions between UVR and pollutants, including the mechanisms of their combined effects leading to disease pathophysiology such as skin cancer. Recent studies, including ours, have indicated that small membrane-bound vesicles known as microvesicle particles (MVP) released from cells in response to various stressors can act as potent signaling agents due to their ability to carry nuclear and cytoplasmic components. We have demonstrated that UVB, due to its ability to generate reactive oxygen species (ROS), produces high levels of the lipid mediator Platelet-activating factor (PAF) agonists and MVP from epithelial cells and skin. Notably, recent studies using PAFR-expressing/null cell lines and pharmacologic/genetic inhibition of ROS, and the enzyme acid sphingomyelinase (aSMase) have implicated the involvement of the PAF-receptor (PAFR) signaling in aSMase activation resulting in UVB- generated MVP (UVB-MVP) release. These UVB-MVP carry bioactive PAF agonists, and mediate UVB-induced delayed immunosuppressive effects. Importantly, we discovered that the PAH Benzo[a]pyrene (BaP) interaction with UVB releases high levels of UVB-MVP and generates increased levels of PAF agonists. As other ROS- generating PAH compounds such as anthracene, chrysene, and pyrene are natural components of environmental pollutants and associated with disease pathophysiologies, including lung/skin cancer mortality, we propose one specific aim to test the hypothesis that these PAHs will exert synergistic effects with UVB in the generation of ROS, PAF-agonists, and MVPs involving the PAFR and acid sphingomyelinase (aSMase) pathways. Aim 1 will use in vitro cell lines and pharmacologic inhibitors to determine the role and mechanisms of these PAHs and UVB in the generation of ROS, PAF, and MVP. Successful completion of this project will (i) define a novel mechanism by which a PAH pollutant can augment UVR-induced effects; and ii) address an important question in photobiology as to how a keratinocyte-specific stimulus can generate systemic signaling effects. Importantly, this supplement project will provide mentorship, required skills and knowledge to a talented applicant and assist her transition to an independent health care research career path in the future.
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).
