Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition and other disorders associated with decreased saliva production. Loss of saliva is symptomatic of Sjgren's syndrome (SS), an autoimmune disease associated with lymphocytic infiltration of the salivary gland, autoantibody production and ultimately tissue degeneration. A commonality between many human autoimmune diseases, including SS, is chronic inflammation whereby sustained accumulation of immune cells promotes tissue degeneration and often leads to other damaging effects including tissue fibrosis, secondary autoimmune diseases (e.g. lupus, rheumatoid arthritis) and the development of lymphoma. A major focus of this proposal is to identify the functional relevance of ?alarmones? that are produced at the site of initial tissue damage and the cellular mechanisms whereby alarmones mobilize the systemic immune system leading to chronic inflammation. Among possible alarmones that initiate autoimmune disease in salivary glands, our laboratory has investigated the effect of localized release of nucleotides, such as ATP, from damaged cells or tissues. We have shown that G protein-coupled P2Y2 receptors (P2Y2R) for ATP and UTP are early responders to released nucleotide alarmones and that knockout of the P2Y2R in a mouse model of SS prevents infiltration of B and T lymphocytes into salivary glands, indicating a loss of the systemic immune response. We hypothesize that chronic inflammation occurs through P2Y2R activation in SS salivary glands, which increases localized chemokine/cytokine levels and attracts peripheral lymphocyte infiltration across the vascular endothelium into salivary glands.
Specific Aims will fully investigate the cell-specific mechanisms that initiate chronic inflammation at the level of P2Y2 receptors in the salivary gland of SS mouse models and test the potential of targeting the P2Y2R in SS mouse models to prevent a systemic immune response.
Specific Aim 1 will address the hypothesis that P2Y2R activation in B and T cells promotes their infiltration and proliferation in salivary glands of SS mouse models thereby contributing to salivary gland dysfunction.
Specific Aim 2 will address the hypothesis that P2Y2R upregulation in salivary epithelium and vascular endothelium contributes to the autoimmune phenotype in SS mouse models.
Specific Aim 3 will evaluate the hypothesis that pharmacological antagonism of P2Y2Rs in vivo reduces chronic inflammation of the salivary glands in two distinct SS mouse models. Successful completion of this project would expedite human studies to target modulation of the P2Y2R in SS to prevent loss of salivary gland function.
Sjgren's syndrome (SS) is a chronic autoimmune disorder characterized by inflammation of salivary and lacrimal glands, and clinical outcomes of dry mouth and eyes. Our research focuses on a cell surface P2Y2 receptor (P2Y2R) for extracellular ATP, the chemical form of energy in a cell that when released from injured or diseased salivary gland tissue contributes to chronic inflammation. The overall goal of these studies is to evaluate whether deletion or inhibition of the P2Y2R decreases the inflammatory response observed in salivary glands of a mouse model of SS, which ultimately will be essential for developing novel treatments for human salivary dysfunction.
|Woods, L T; Camden, J M; Khalafalla, M G et al. (2018) P2Y2 R deletion ameliorates sialadenitis in IL-14?-transgenic mice. Oral Dis 24:761-771|
|Voynova, Elisaveta; Mahmoud, Tamer; Woods, Lucas T et al. (2018) Requirement for CD40/CD40L Interactions for Development of Autoimmunity Differs Depending on Specific Checkpoint and Costimulatory Pathways. Immunohorizons 2:54-66|
|Kayes, Timothy Daniel; Weisman, Gary A; Camden, Jean M et al. (2016) New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland. J Immunol 197:2119-30|
|Woods, Lucas T; Camden, Jean M; El-Sayed, Farid G et al. (2015) Increased Expression of TGF-? Signaling Components in a Mouse Model of Fibrosis Induced by Submandibular Gland Duct Ligation. PLoS One 10:e0123641|
|Nadel, Yael; Lecka, Joanna; Gilad, Yocheved et al. (2014) Highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5'-(? or ?)-thio-(?,?- or ?,?)-methylenetriphosphate scaffold. J Med Chem 57:4677-91|
|Weisman, Gary A (2014) Why do male mice spit soluble enzymes that hydrolyze extracellular nucleotides? Focus on ""Prostatic acid phosphatase is the main acid phosphatase with 5'-ectonucleotidase activity in the male mouse saliva and regulates salivation"". Am J Physiol Cell Physiol 306:C997-8|
|Liao, Zhongji; Cao, Chen; Wang, Jianjie et al. (2014) The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells. J Biomed Sci Eng 7:1105-1121|
|El-Sayed, Farid G; Camden, Jean M; Woods, Lucas T et al. (2014) P2Y2 nucleotide receptor activation enhances the aggregation and self-organization of dispersed salivary epithelial cells. Am J Physiol Cell Physiol 307:C83-96|
|Yelovitch, Shir; Barr, Haim M; Camden, Jean et al. (2012) Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist. J Med Chem 55:7623-35|
|Weisman, Gary A; Woods, Lucas T; Erb, Laurie et al. (2012) P2Y receptors in the mammalian nervous system: pharmacology, ligands and therapeutic potential. CNS Neurol Disord Drug Targets 11:722-38|
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