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Principal Investigator: Gosse, Julie Ann
Institute Receiving Award University Of Maine Orono
Location Orono, ME
Grant Number R15ES034567
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 11 Aug 2022 to 31 Jul 2025
DESCRIPTION (provided by applicant): People are widely exposed to high (mM) doses of the positively-charged antibacterial agent cetylpyridinium chloride (CPC) via janitorial and personal care products and foods treated with CPC, yet little is known about its toxicology in humans, especially below the critical micelle concentration (~900 µM). While applied CPC is retained in the oral mucosa and is released into saliva such that low-µM CPC continuously bathes oral cells, there is a dearth of publications on the effects of CPC on eukaryotes. The Gosse lab has discovered that exposure to non- cytotoxic, low-µM CPC concentrations potently inhibits signaling of mast cells, key players in the immune and nervous systems that share core signaling elements with T cells and other cell types. In mast cells, upon antigen crosslinking of cell surface receptors, a tyrosine phosphorylation cascade ensues, leading to activation of PLCγ1 enzymatic cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) and subsequent Ca2+ mobilization and degranulation: microtubule transport of granules to the cell surface, leading to exocytosis of bioactive substances such as histamine and serotonin. Analogous aggregation of T cell receptors leads also to tyrosine phosphorylation, Ca2+ mobilization, and downstream T cell function. CPC effects on both mast and T cell function will be determined. Preliminary data have led to the hypothesis that CPC inhibits immune cell function by electrostatically interfering with phosphorylation and PIP2, leading to displacement of PIP2-binding proteins, disrupted nanoscale clustering of PIP2, muted release of Ca2+ from endoplasmic reticulum (ER) stores, and, thereby, inhibited inflow of Ca2+ to the cytosol and extinguished microtubule polymerization. CPC effects on phosphorylation will be assessed by multiple means. Confocal microscopy and plate reader experiments will define CPC effects on sub-cellular localization and function of PLCγ1; of PLCγ1 product inositol 1,4,5-trisphosphate which initiates release of ER Ca2+; of Ca2+ dynamics in ER, mitochondria, Golgi, and cytosol; and of key elements downstream of Ca2+ including protein kinase C, phospholipase D, and microtubules. Whether CPC directly displaces PIP2 from its partner proteins will be measured. Super-resolution fluorescence photoactivation localization microscopy will interrogate nanoscale CPC effects on PIP2 clusters and other protein interactions crucial to immune function, including co-localization of Git1 regulator with tubulin as well as PIP2 with machinery required for granule exocytosis. This research will uncover the mechanisms underlying CPC disruption of immune cell function in order to fulfill an urgent need by providing insights into CPC effects on environmental human health.
Science Code(s)/Area of Science(s) Primary: 05 - Signal Transduction
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Michael Humble
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