Cellular senescence contributes to salivary gland dysfunction in Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease that affects millions of Americans, in which salivary gland integrity and function are impaired, leading to dry mouth as the major clinical manifestation. The insufficient saliva production also can severely compromise multiple facets of oral health and overall quality of life. To date, there is no known cure or effective treatment for SS. Previous studies on SS patients have demonstrated the presence of cellular senescence in the salivary glands. Moreover, the proportion of senescent salivary gland cells, particularly those located in the salivary gland stem cell- residing ductal compartments, strongly correlates with the disease severity, accompanied by a decline in the function of salivary gland stem cells. Consistent with this, our preliminary studies with spontaneous and inducible mouse models of SS revealed an increased number of senescent cells in the submandibular glands, coupled with a reduced stemness of salivary gland stem cells. Notably, administration of a senolytic drug to non-obese diabetic (NOD) mice, a well-defined spontaneous model of SS significantly reduced salivary gland senescent cells and improved hyposalivation during SS progression. The objective of this proposed project is to determine the previously unexplored impact of cellular senescence on SS-associated salivary gland disorder and salivary gland stem cell activity, with the long-term goal of developing effective and targeted interventions for this disease. Based on the literature and our preliminary results, we hypothesize that cellular senescence plays a detrimental role in salivary gland secretory function in SS, by exacerbating salivary gland inflammation and diminishing salivary gland stem cell activities. This hypothesis will be tested through the following specific aims: In Aim 1, we will determine the impact of cellular senescence on SS-associated xerostomia and sialadenitis through two distinct approaches, including senolytic drug-based elimination of senescent cells in NOD mice and herpes simplex virus Ɩ thymidine kinase-mediated ablation of senescent cells in p16-3MR genetically engineered mice with SS induction; In Aim 2, we will elucidate the impact of cellular senescence on the expansion and differentiation of salivary gland stem cells and comprehensively characterize the transcriptomic profile of these cells in both SS mouse models. Successful completion of this study will provide a critical and rational foundation for the development of effective therapeutic strategies for SS- associated exocrinopathy and shed light on the treatment of xerostomia caused by other factors such as medications or aging, as well as other autoimmune diseases that share similar pathogenic mechanisms with SS. Project Number: 1R21DE034091-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Jing Zhou | Institution: ADA FORSYTH INSTITUTE, INC., Somerville, MA | Award Amount: $248,750 | Activity Code: R21 | Study Section: Oral, Dental and Craniofacial Sciences Study Section[ODCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11138212