Sjgren's syndrome (SS) is a chronic autoimmune disease affecting millions of Americans, in which salivary glands are the primary target of autoreactive T cells, leading to hyposalivation, the major disease hallmark. Hyposalivation (dry mouth) causes a variety of oral health issues and severely compromises quality of life. SS has no cure and current treatments are predominantly palliative. Failure of therapies for SS are inextricably linked to the inability to control autoinflammation; thus, we propose to investigate both simultaneously. To achieve sustainable salivary secretion, development of approaches to simultaneously enhance endogenous salivary gland regeneration and protect the glands from further injury from autoimmune inflammation are critically needed. Our preliminary studies strongly suggest that there are protective actions provided by intermittent fasting (IF) in SS. In non- obese diabetic (NOD) mice, a well-defined spontaneous model of SS, IF enhances the proliferation of salivary gland stem cells, and upregulates Wnt and Notch signaling and Peroxisome Proliferator- Activated Receptor-driven fatty acid oxidation, which are critically involved in the expansion and differentiation of multiple stem cell types. It also mitigates autoreactive T helper 1, T helper 17 and cytotoxic T cell responses in the salivary gland-draining lymph nodes. The objective of this proposed project is to determine the previously unexplored impact of IF on the activity of endogenous salivary gland stem/progenitor cells and autoimmune inflammation in SS to unravel the underlying molecular and cellular mechanisms of IF benefits, with the long-term goal of developing effective and targeted therapies to fundamentally improve salivary gland function. Based on the literature and our preliminary results, we formulated the central hypothesis that IF exerts beneficial actions on salivary gland restoration through promoting endogenous salivary gland regeneration and diminishing T cell mediated autoimmune inflammation in SS. This hypothesis will be tested through the following specific aims:
In Aim 1, we will dissect the potential molecular mechanisms for the impact of IF on the proliferation and differentiation of salivary gland stem cells in the NOD mouse, a spontaneous model of SS;
In Aim 2, we will assess the impact of IF on the self-expansion and cellular plasticity of ductal salivary gland progenitor cells and acinar cells, the function and plasticity of T cell subsets, and the attenuation of autoimmune inflammation in the salivary tissues, using lineage tracing mouse models and an inducible model of SS. Successful completion of this study will provide new targets for the development of effective new therapeutics for SS-like exocrinopathy, as well as provide insight into the treatment of xerostomia caused by radiation, medications or aging, and other autoimmune diseases that share similarities in their pathogenesis with SS.
Sj?gren?s syndrome-associated xerostomia greatly compromises the oral health and the quality of life of 2-4 million Americans because of devastating loss of saliva and severe dry mouth. SS is an autoimmune disease and destruction of the salivary glands, and failure of therapies to restore their function, is the result of our inability to control autoimmune inflammation. Completion of this proposed project will contribute to the development of effective and targeted therapeutic strategies to fundamentally restore salivary gland integrity and function.