Investigating the Role of Histamine and HRH1 in Mucus Secretion in the Salivary Glands - Histamine is a signaling molecule produced by host cells and bacteria, acting through four receptors (HRH1, HRH2, HRH3, HRH4), each with tissue-specific roles. HRH1 is known for its pro-inflammatory effects in the airway epithelium, but our data suggests it plays a non-inflammatory role in mucus secretion in the gut and salivary glands. Mucus is essential for oral health, influencing hydration, lubrication, and protection while affecting the oral microbiome. Disruptions in histamine signaling, such as through antihistamines or microbial changes, are linked to reduced salivation and dry mouth, suggesting a role for histamine in oral mucus secretion. HRH1, the only histamine receptor in salivary glands, is expressed on the apical and basolateral membranes of mucous acini. Our data shows that histamine stimulates mucus secretion from salivary gland organoid monolayers without eliciting pro-inflammatory responses seen in other organs, suggesting HRH1-mediated mucus release supports tissue homeostasis. This proposal aims to explore how HRH1 signaling regulates salivary gland mucus secretion and the role of microbial-derived histamine, specifically from the probiotic Limosilactobacillus reuteri. We hypothesize that bacterial histamine activates HRH1 in salivary glands, stimulating mucus secretion to support oral health. Aim 1 focuses on the signaling cascade initiated by HRH1 activation in mouse salivary gland organoids, examining PLC-IP3 pathways, intracellular calcium signaling, and transcriptional changes to understand histamine's role in mucin secretion and gene regulation. Aim 2 evaluates how L. reuteri-derived histamine impacts mucus secretion and oral health. Using wild-type and histamine- deficient L. reuteri strains, we will assess bacterial histamine’s effect on salivary gland secretion in organoid and mouse models, confirming receptor-specific effects with HRH1 antagonists. This research could inform therapeutic applications for xerostomia and other oral health issues by revealing how microbial-derived histamine and HRH1 activation influence salivary gland function. The Medical University of South Carolina (MUSC) offers a collaborative environment with resources and mentorship to support these objectives and Selene’s (the PI’s) career. Selene’s long-term goal is to specialize in host-microbe interactions, gaining expertise in techniques like cell culture, histology, and mouse models. During postdoctoral training, she aims to publish papers, improve writing, build networks, and receive mentorship from experts like Dr. Engevik and Dr. Kern, while gaining experience in grant writing and teaching to prepare for an academic career. Collectively, these experiments, the research environment, and the training plan outlined will enhance our understanding of histamine in oral health, provide insight for novel therapeutic targets to improve the oral environment, and prepare Selene for a career in science academia, aligning well with the NIDCR’s mission to train scientists and advance research that improves oral health.
