Resolution of Cytokine-Mediated Salivary Gland Inflammation

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DESCRIPTION (provided by applicant): Sj�gren's Syndrome (SS) is an autoimmune disease affecting 1% of the population. The hallmarks of SS are dry mouth and dry eyes. Such symptoms are typically clinically detectable only after salivary and lacrimal glands display chronic inflammation, a point at which current therapies have no benefit. Although extensive investigation has been done to understand the ethiopathogenesis of SS, the causes or cures for the disease are still unknown. Recent studies demonstrate that human and animal cells convert ?-3 polyunsaturated fatty acids (PUFAs) into resolvins (Rv), which are new, highly potent, anti-inflammatory agents that control the resolution of inflammation in models colitis, periodontitis and corneal inflammation. Additionally, our recent findings indicate that the RvD1 receptor ALX is expressed in normal salivary cells, as well in cell lines of salivary origin. In salivary epitheium, RvD1 blocks TNF�-mediated disruption of acinar formation and enhances epithelial integrity via PI3k/Akt pathways. Furthermore, treatment of a SS mouse model with AT-RvD1 before disease onset (at 4 weeks of age) prevents secretory dysfunction and lymphocytic infiltration in submandibular glands that occurs during onset of the disease (at 16-weeks of age). Therefore, the proposed studies will elucidate the mechanisms whereby RvD1 and AT-RvD1 prevent inflammatory dysfunction and restore salivary epithelial integrity, using accepted in vitro and in vivo salivary models of SS. We hypothesize that resolution of inflammation in salivary glands can prevent, and could help manage, symptoms of SS. We plan to address the following: Aim 1: To characterize the pathways involved in the generation of RvD1 in salivary glands. We will investigate whether enzymes and metabolites involved in the biosynthesis of RvD1 are altered during the progression of SS. Aim 2: To investigate the downstream signaling pathways triggered by RvD1 in salivary glands. We will study the mechanisms by which RvD1 binds to the ALXR and activates cell migration, cell polarity, and cell survival (in primary mouse SMG cells and in salivary cell lines). Aim 3: To evaluate the efficacy of the RvD1 treatment (i.e., the abiliy to prevent inflammation and secretory dysfunction) in SS mice models. We believe a better understanding of RvD1 biogenesis, signaling, and treatment could reduce the progress of SS in earlier stage patients and lead to improved symptom management for advanced stage patients.