Sjogren's syndrome (SS) is an autoimmune disorder characterized by inflammation and destruction of lacrimal and salivary glands leading to decreased fluid secretion (xerostomia) often associated with lymphocytic infiltration of the tissue. Salivary gland biopsies from SS patients show a marked expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in venules surrounded by infiltrating CD4+ T cells. Our studies have shown that a P2Y2 nucleotide receptor (P2Y2R) is up-regulated in tissues, including salivary gland, due to stress and injury and regulates adhesion molecule expression and inflammatory responses. However, it is unknown whether P2Y2R up-regulation regulates the expression of specific adhesion molecules leading to lymphocyte infiltration in salivary gland. Since P2Y2R agonists ATP and DTP are released from damaged or stressed cells, P2Y2R expression and activation in vivo undoubtedly augments the deleterious effects of other pro-inflammatory agents in SS. We hypothesize that chronic inflammation of salivary glands in SS is mediated by P2Y2R signaling pathways leading to the up-regulation of cell adhesion molecules that promote the binding of lymphocytes, a novel pathway that can be exploited to retard the development of SS. Proposed studies will test the hypothesis that specific cell adhesion molecules are up-regulated by P2Y2R activation to promote lymphocyte adherence to salivary gland cells (Specific Aim 1). Other studies will define the signaling pathways involved in P2Y2R-mediated expression of cell adhesion molecules and lymphocyte adherence to salivary gland cells, including the contribution of growth factor receptor transactivation and matrix metalloproteases (Specific Aim 2). In addition, we will determine whether activation of P2Y2Rs in vivo mediates adhesion molecule expression to promote lymphocyte infiltration into salivary gland (Specific Aim 3A). Furthermore, studies will investigate whether adhesion molecule expression and lymphocyte infiltration into salivary glands of the NOD.B10 mouse model of SS can be inhibited by silencing of the P2Y2R in vivo (Specific Aim 3B). These studies should lead to better therapeutic strategies for minimizing autoimmune-associated inflammation of salivary gland that contributes to xerostomia in patients with SS. ? ? ?
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