Fellowship for Andrew Douglas McCall: Vascular Remodeling and the Role of PECAM-1 in Sjogren Syndrome

DESCRIPTION (provided by applicant): Saliva plays a critical role in maintaining proper oral health. Hyposalivation can severely reduce the quality of life for an individual.1,2 A common cause of hyposalivation is Sjogren's syndrome (SS), an autoimmune disorder characterized by lymphocytic infiltration into the salivary glands.3 Although many laboratories around the world are investigating SS,4-6 little is known about the role of vascular remodeling (angiogenesis) in the pathogenesis of this disease. Previous studies indicate that mediators of angiogenesis (i.e., vascular endothelial growth factors and nitric oxide) are upregulated in the salivary glands and saliva of SS patients.7,8 These findings suggest that angiogenesis is occurring during the progression of this disorder. Another important contributor to angiogenesis is the cell adhesion protein, platelet endothelial cell adhesion molecule-1 (PECAM-1),9,10 whose expression has not been studied in SS. PECAM-1 can also impact the trafficking of lymphocytes to the salivary gland,11,12 potentially leading to a more severe SS phenotype. The goal of this project is understand how PECAM-1 influences angiogenesis and lymphocyte trafficking in the progression of SS. To conduct this research, we will use human minor salivary glands with SS and a mouse model of SS. Together, the following studies will further our understanding of SS pathogenesis, and may eventually lead to the development of novel therapies for this disorder: Aim 1: To investigate signs of angiogenesis in salivary glands with and without SS. Blood vessel coverage area and expression levels of endothelial markers will be analyzed by fluorescent microscopy, RT-PCR and Western blot. Aim 2: To determine PECAM-1 isoforms, post-translational modifications and signaling pathways in salivary glands with and without SS. PECAM-1 isoforms, post-translational modifications, and signaling partners will be analyzed by RT-PCR, tandem mass spectrometry, and co-immunoprecipitation. Aim 3: To analyze the role of PECAM-1 during lymphocyte transmigration in mouse major salivary glands with SS. PECAM-1 will be functionally blocked in vitro and in vivo using blocking antibodies and transmigration will be quantified.