The role of the P2Y2 nucleotide receptor in salivary gland regeneration
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Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition, and other disorders that are associated with decreased saliva production. Over the past decade, progress has been made in cell-based reconstitution strategies for salivary glands. Understanding the mechanisms and signaling pathways that regulate the salivary gland reconstitution process is a necessity to enhance the ongoing efforts to develop better regenerative therapies for damaged salivary glands. The P2Y2 nucleotide receptor (P2Y2R), a G protein-coupled receptor equipotently activated by ATP and UTP, is upregulated in a variety of tissues, including salivary gland epithelium, in response to injury or stress and is proposed to play important roles in the regeneration of a variety of tissues. The results presented in this dissertation indicate that P2Y2R activation with UTP enhances the migration, aggregation and self-organization of dispersed salivary epithelial cells forming spheres that display characteristics similar to differentiated acini in salivary glands. Moreover, our data suggest that the afore- mentioned P2Y2R-mediated response s depend on the transactivation of the epidermal growth factor receptor (EGFR) via a disintegrin and metalloproteinases (ADAM10/ADAM17) and the [alpha-5 beta-1] integrin/Cdc42 Rho GTPase signaling pathway. This study sheds light on the P2Y2R as a target in salivary gl and reconstitution strategies and introduces [alpha-5 beta-1] integrin and Cdc42 as novel downstream components in the P2Y 2 R-mediated signaling network. Future studies will optimize the activation of P2Y2R-mediated signaling pathways to promote the self- organization of salivary epithelial cells into acinar-like spheres that secrete saliva components and have utility for replacement of salivary gland tissue damaged by autoimmune disease or radiation therapy used to treat head and neck cancers.
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