CAREER: The roles of zinc in taste cell regeneration and sweet taste signaling

About This Grant

This project will identify specific roles that zinc plays in the sensation of taste. Zinc is a micronutrient essential for all life forms. Zinc supplementation is a proven method to treat taste loss, and zinc is a potent inhibitor of sweet taste, but the underlying mechanisms are not known. Zinc transporters are ‘chokepoint’ proteins located in the cell membrane that mediate the movement of zinc into and out of cells and subcellular compartments, thereby regulating intracellular zinc concentration. The key zinc transporters and other zinc-regulated proteins that regulate taste cell regeneration will be identified using gene expression studies in taste buds of mice fed a zinc-deficient diet and by targeted gene deletion of zinc transporters in mouse taste organoids, a tissue culture system that ‘mimics taste buds in a dish.’ To determine how zinc inhibits sweet taste, the changes in behavioral, neural and cellular responses to sweeteners in knockout mice and in taste organoids that lack a sweet taste-cell-specific zinc transporter gene will be determined. The integrated educational and outreach programs aim to train the next generation of STEM workforce and promote nutritional literacy to the public. To this end, summer internships and mentoring will be provided to community college students wishing to transition into four-year colleges, and nutrition literacy will be provided through scientific demonstrations at community outreach programs and at classes for adults. Ultimately, this research will help develop improved methods to treat taste loss and prevent overconsumption of calorie-dense, sugar-sweetened foods and beverages in humans. This project uses gene expression, cell physiology, histology, taste nerve recordings and taste behavior analysis to advance understanding of the roles of zinc transporters and other zinc-regulated proteins in taste cells. CRISPR knockout array screens of zinc transporters in mouse taste organoids, followed by single cell gene expression, will be used to identify key taste-stem-cell-expressed zinc transporters and zinc-regulated genes ex vivo. The results of these experiments will help identify key zinc transporters, zinc-regulated proteins and signaling pathways that are required for taste cell regeneration. In addition, zinc-regulated genes will be identified in vivo by single-cell and spatial gene expression of taste papillae of mice fed a zinc-deficient diet. The roles of the sweet-taste-cell-expressed zinc transporter Slc39a8 in behavioral responses and taste nerve responses to sweeteners will be determined by comparing the Slc39a8 conditional knockout mouse strain and control strain. Sweetener-stimulated zinc and calcium fluxes in taste organoids cultured from both mice strains will be measured, and the roles of extracellular versus intracellular zinc will be studied using cell membrane -impermeant and -permeant zinc chelators, respectively. Together, the combination of behavioral, electrophysiological and mechanistic studies will shed light on how zinc inhibits sweet taste signaling. The findings from both tasks will be highly translatable to related tissues such as the skin and olfactory and intestinal epithelia where zinc plays important roles in development, regeneration, and metabolism. This project is jointly funded by the BIO-IOS-Physiological Mechanisms and Biomechanics Program, the BIO-IOS-Activation Program, and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.