Over 60,000 cases of head and neck cancer are diagnosed in the US annually with typical treatment including surgery and radiation. Radiation therapy causes collateral damage to nearby normal tissues, particularly the salivary glands, which results in chronic hyposalivation and xerostomia. Currently only limited palliative treatment options exist, therefore the mechanisms behind radiation-induced salivary gland dysfunction should be investigated further. It is well-established that radiation causes production of reactive oxygen species (ROS), which leads to secretion of pro-inflammatory signals (i.e. cytokines, eicosanoids) to recruit immune cells to aid in tissue repair. The P2X7 receptor (P2X7R) is highly expressed on salivary epithelial cells, mediates ROS, interleukin-1? and prostaglandin E2 production and is activated following radiation. P2X7R is a purinergic receptor activated by high levels of extracellular ATP (>100?M) that are often secreted during inflammation. While a select number of cytokines and eicosanoids have been investigated following radiation, the network of inflammatory signals and phagocytic cell activity has not been fully elucidated, nor has the role of the P2X7R in these pathways. The goal of this proposal is to evaluate the integrated network of inflammatory signals, the downstream signaling cascades induced, the predominant phagocytic cell type and the role of the P2X7R in these processes in the salivary gland following radiation exposure. We hypothesize that radiation-induced salivary gland dysfunction occurs due to P2X7R-mediated pro-inflammatory signaling, and tissue-resident macrophages are the predominant phagocytic cell type in salivary tissue. To test this hypothesis, we will unbiasedly quantify the full network of inflammatory signals (i.e., cytokines and eicosanoids) produced by salivary epithelial cells following radiation exposure and determine downstream pathways induced by these signals through evaluation of receptor binding and activation of intracellular signaling cascades. Further, we will evaluate the predominant phagocytic cell population, the inflammatory signals generated following engulfment of radiation-induced apoptotic cells and determine the activity of tissue-resident macrophages post-radiation. The role of the P2X7R will be determined by comparing the results of the proposed experiments of wild type mice to that of P2X7R knockout (P2X7R-/-) or P2X7R antagonist (A438079)-treated mice. Previous work has shown that P2X7R knockdown allows for sustained salivary function following radiation in mice and inhibition with the P2X7R antagonist may prove to be a novel therapeutic target for normal tissue preservation during radiation therapy. The long-term outcomes of this project will provide an unbiased understanding of the acute and chronic inflammatory response occurring in salivary epithelial cells following radiation damage and uncover the role of the P2X7 receptor in radiation-induced inflammation. This may impact fields beyond salivary gland research, as these results should be expandable to other types of tissues and forms of tissue damage.

Public Health Relevance

Radiation therapy is a common cancer treatment that causes collateral damage to nearby normal tissues, particularly the salivary glands, which leads to chronic hyposalivation, a serious side-effect for head and neck cancer patients undergoing treatment. Currently only palliative treatment options exist, supporting the need for further research on this topic. This research project will help define the inflammatory response to radiation exposure in the salivary gland, which will help identify novel therapeutic targets to aid in normal tissue preservation during radiation treatment that could be expandable to other tissue types or types of tissue damage.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Predoctoral Individual National Research Service Award (F31)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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University of Arizona
Earth Sciences/Resources
United States
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