PROJECT SUMMARY Tuft cells are rare cholinergic chemosensory epithelial cells capable of producing an unusual spectrum of biological effector molecules, such as interleukins, eicosanoids and neurotransmitters. Previous studies have shown that tuft cells are capable of triggering immune responses in different organs (e.g., intestine and airways) via G protein-coupled receptor-dependent pathways, involving components of chemosensory transduction. Although tuft cells have been detected in salivary glands, their functions in this organ are unknown. The aims of this project are designed to utilize modern technologies to explore tuft cells biology in salivary gland epithelium as well as their role in innate and adaptive immunity. The K99 phase proposes to (1) to investigate tuft cell distribution and function in salivary gland epithelium through advanced microscopic techniques as well as in vivo experiments; (2) to determine tuft cell chemosensory components in salivary gland epithelium using single cell analysis; (3) to determine the effects of tuft cell on salivary gland innate immunity using tuft cell ablation in vivo model. During this time the candidate will complete mentored training in molecular immunology and biology, high-resolution microscopy, single cell RNA sequencing and spatial transcriptomics as well as courses in professional development. The independent R00 phase will investigate the role of tuft cells in salivary gland adaptive immunity utilizing Sjögren’s syndrome-like mouse models and human specimens. Together, the new generated information will allow a better understanding of tuft cell biology in salivary gland and allow therapeutic targets for salivary gland diseases.