Transaction Description:
LLUMINATING THE ROLE OF THE NOVEL G PROTEIN-COUPLED P2Y10 RECEPTOR IN SJÖGREN’S DISEASE PATHOPHYSIOLOGY - THREE G PROTEIN-COUPLED RECEPTORS (GPCRS) FOR LYSOPHOSPHATIDYLSERINE (LYSOPS), I.E., P2Y10, GPR174, AND GPR34, WERE RECENTLY IDENTIFIED. STUDIES IN MICE HAVE UNCOVERED IMMUNOMODULATORY FUNCTIONS OF LYSOPS, AND ASSOCIATIONS WITH AUTOIMMUNE CONDITIONS HAVE BEEN ESTABLISHED, INCLUDING GRAVES’ DISEASE, ADDISON’S DISEASE, AND AUTOIMMUNE THYROID DISEASES. THE P2Y10 RECEPTOR (P2Y10R) WAS INITIALLY IDENTIFIED AS A MEMBER OF THE P2Y FAMILY OF NUCLEOTIDE RECEPTORS BASED ON STRUCTURAL SIMILARITIES. HOWEVER, THE ABILITY OF NUCLEOTIDE LIGANDS TO ACTIVATE P2Y10R REMAINS UNCERTAIN. THIS PROJECT AIMS TO ADDRESS PREVIOUS STUDY LIMITATIONS TO DETERMINE P2Y10R LIGAND SPECIFICITY. THE PATHOPHYSIOLOGICAL AND IMMUNOMODULATORY FUNCTIONS OF LYSOPS RECEPTORS VARY WITH DISEASE MODEL AND CELL TYPE, WHICH MAY BE ATTRIBUTED TO THE LYSOPS SPECIES PRESENT. SPECIES OF LYSOPS HAVE VARIOUS FATTY ACID CHAINS LOCATED AT EITHER THE SN-1 OR SN-2 POSITION, AND CHAIN LENGTH CAN DICTATE THE IMMUNOLOGICAL RESPONSE BASED ON PREFERENTIAL RECEPTOR BINDING. SJÖGREN’S DISEASE (SJD) IS A CHRONIC, INFLAMMATORY AUTOIMMUNE DISEASE CHARACTERIZED BY LYMPHOCYTIC INFILTRATION OF THE LACRIMAL AND SALIVARY GLANDS, RESULTING IN DRY EYE AND DRY MOUTH, RESPECTIVELY. BEYOND GLANDULAR INVOLVEMENT, SJD IS A SYSTEMIC DISEASE THAT IMPACTS MANY EXOCRINE AND NON-EXOCRINE TISSUES, WITH PULMONARY MANIFESTATIONS OBSERVED IN MORE THAN 20% OF ALL SJD PATIENTS. IN ADDITION TO GENETIC FACTORS, SJD IS TRIGGERED BY ENVIRONMENTAL EXPOSURES, INCLUDING VARIOUS VIRAL INFECTIONS. OUR PRELIMINARY DATA IN HUMANS AND MICE SUGGEST AN ASSOCIATION BETWEEN P2Y10R AND THE SJD PHENOTYPE. WE FOUND THAT GPR174, P2RY10, AND THE LYSOPS-PRODUCING ENZYME, PHOSPHOLIPASE A1A (PLA1A), BUT NOT GPR34, ARE UPREGULATED IN PAROTID AND MINOR SALIVARY GLANDS OF SJD PATIENTS COMPARED TO NON-SJD CONTROLS. P2Y10R AND GPR174 RECEPTORS ARE EXPRESSED PREDOMINANTLY IN IMMUNE CELLS AND LYMPHOID ORGANS SUCH AS THE SPLEEN AND BONE MARROW. P2Y10R EXPRESSION DEPENDS ON THE ETS TRANSCRIPTION FACTORS PU.1 AND SPI-B, KNOWN B CELL RECEPTOR SIGNALING MEDIATORS THAT PROMOTE B CELL MATURATION. B CELLS PLAY AN ESSENTIAL ROLE IN THE PATHOGENESIS OF SJD. INDICATORS OF B CELL HYPERACTIVITY IN SJD INCLUDE THE PRODUCTION OF AUTOANTIBODIES, HYPERGAMMAGLOBULINEMIA, AND THE DEVELOPMENT OF B CELL LYMPHOMAS. SINGLE-CELL RNA- SEQUENCING (SCRNA-SEQ) DATA FROM THE MINOR SALIVARY GLAND (MSG) BIOPSIES OF SJD AND NON-SJD SUBJECTS REVEALED THAT P2RY10 IS MOST ABUNDANT IN B CELLS, T CELLS, AND NK CELLS, WITH LOWER EXPRESSION IN PLASMA CELLS AND MACROPHAGES. AMONG THESE, P2RY10 WAS MOST UPREGULATED IN T CELLS IN SJD GLANDS COMPARED TO CONTROLS. THOUGH B CELLS HAVE RECEIVED MUCH ATTENTION IN THE STUDY OF SJD, T CELLS HAVE GARNERED RECENT INTEREST AND ARE IMPORTANT TO DISEASE PROCESSES. OUR PRELIMINARY DATA IN MICE INDICATE THAT P2Y10RS ARE PRESENT IN THE SUBMANDIBULAR GLANDS OF IL-14ΑTG SJD-LIKE MICE AT HIGHER LEVELS THAN AGE-MATCHED WILD-TYPE C57BL/6 MICE AND CAN BE ACTIVATED BY LYSOPS. SPATIAL TRANSCRIPTOMIC ANALYSIS REVEALED THAT P2RY10 EXPRESSION IS LOCALIZED TO ECTOPIC GERMINAL CENTERS IN THE IL-14ΑTG SUBMANDIBULAR GLAND. THESE DATA SUGGEST AN ASSOCIATION OF P2Y10R WITH THE SJD PHENOTYPE IN HUMANS AND MICE AND WARRANT FURTHER INVESTIGATION. WE PROPOSE TO USE BIOINFORMATIC AND IN VIVO TECHNIQUES TO ELUCIDATE THE ROLE OF P2Y10R IN SJD PATHOPHYSIOLOGY. UNDERSTANDING THE ROLE OF P2Y10R IN SJD PATHOPHYSIOLOGY COULD ESTABLISH A DRUGGABLE TARGET FOR SJD PHARMACOTHERAPY.
