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Principal Investigator: GARY Andrew WEISMAN
Organization: UNIVERSITY OF MISSOURI-COLUMBIA
Fiscal Year: 2020
Award: $232,102
Funding agency: National Institute of Dental and Craniofacial Research
Salivary gland dysfunction is symptomatic of Sjögren’s syndrome (SS), an autoimmune disease associated with lymphocytic infiltration of the salivary gland. 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. A major focus of the parent grant for this supplement is to identify the functional relevance of extracellular nucleotide “alarmones” that are produced at the site of initial tissue damage. 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 in SS salivary glands is mediated by P2Y2Rs through activation of several signaling pathways through its distinct structural motifs. The Specific Aims of the parent grant are to investigate the cell mechanisms that initiate chronic inflammation at the level of P2Y2 receptors and to test the potential of targeting the P2Y2R in SS to prevent a systemic immune response. Directly relevant to this supplemental proposal, we have identified an Arg-Gly-Asp (RGD) sequence in the 1st extracellular loop of the P2Y2R and conclusively demonstrated its direct interaction with and activation of RGD-binding integrins. Corona Virus Disease 2019 (COVID-19) is a highly infectious disease caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) to attach to cells via a receptor-binding domain (RBD) located on its Spike (S) protein. Interestingly, the S protein RBD also contains an RGD motif, suggesting that RGD-binding integrins may be co-receptors with ACE2 for S protein. Thus, considering the presence of an RGD motif in the SARS-CoV-2 S protein RBD and the established interaction between ACE2 and integrins, we hypothesize that P2Y2Rs and RGD-binding integrins modulate SARS-CoV-2 entry. In addition to lung tissues, ACE2 is also expressed in oral epithelial cells, particularly in the tongue. This finding suggests that the oral cavity is susceptible to SARS-CoV-2 infection, which presents a significant concern for potential infections associated with dental procedures. Thus, this supplement offers a unique opportunity to test the novel hypotheses that SARS-CoV-2 entry in oral epithelial cells is dependent on RGD-containing S protein association with RGD-binding integrins that act as a co-receptor with ACE2 and that this interaction underlying COVID-19 can be modulated by RGD-containing P2Y2Rs that bind to these same integrins. These studies potentially offer an innovative translational approach whereby patients undergoing dental procedures could be administered a P2Y2R or integrin modulator via mouthwash or mouth spray that would reduce SARS-CoV-2 entry into oral epithelial cells, thereby preventing viral transmission.
Terms: <2019 novel coronavirus><2019-nCoV><ATP Receptors><Address><Adhesion Molecule><Administrative Supplement><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Arg-Gly-Asp><Arginine-Glycine-Aspartic Acid Cell Adhesion Domain><Autoimmune Diseases><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Body Tissues><Buccal Cavity><Buccal Cavity Head and Neck><CD143 Antigens><COVID-19><COVID19><Carboxycathepsin><Cavitas Oris><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell membrane><Cell surface><Cell-Adhesion Molecule Receptors><Cell-Adhesion Protein Receptors><Cells><Chronic><Communicable Diseases><Complex><Coupled><Crowns><Cytoplasmic Membrane><Dental Care><Dental Procedure><Dental crowns><Dipeptidyl Peptidase A><Dysfunction><Envelope Protein><Epithelial Cells><Functional disorder><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Glycoproteins><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><HIV-1><HIV-I><HIV1><Hantavirus Infections><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Immune><Immune response><Immunes><Immunological response><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Infiltration><Inflammation><Inhalation><Inhaling><Integrin Binding><Integrin alpha-5 beta-1><Integrin alpha5beta1><Integrin α5β1><Integrins><Integrins Extracellular Matrix><Kininase A><Kininase II><Knock-out><Knockout><Lung Parenchyma><Lung Tissue><Lymphocyte><Lymphocytic><Mediating><Modern Man><Molecular Interaction><Mouth><Mouthwash><NIDCR><NIDR><Nasal Epithelium><National Institute of Dental Research><National Institute of Dental and Craniofacial Research><Nucleotides><Oral><Oral cavity><P2Y(2) receptor><P2Y2 receptor><Pathogenesis><Patients><Peptidyl-Dipeptidase A><Physiopathology><Plasma Membrane><Platelet Glycoprotein Ic/IIa><Prevent viral transmission><Proteins><RGD (sequence)><RGD Cell Adhesion Domain><RGD Domain><RGD Motif><RGD Tripeptide Sequence><RGD peptide><RGD tripeptide><Receptor Activation><Receptor Protein><Role><Route><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Salivary Glands><Salivary Glands Head and Neck><Severe acute respiratory syndrome coronavirus 2><Signal Pathway><Site><Sjogren's Syndrome><Sjogrens><Sjögren Syndrome><Structure><Structure of parenchyma of lung><T-Cells><T-Lymphocyte><Testing><Tissues><Tongue><Transmission><VLA-5><VLA-5 Receptors><Viral><Virus><Wuhan coronavirus><arginyl-glycyl-aspartic acid><autoimmune disorder><cell adhesion protein><corona virus disease 2019><coronavirus disease 2019><dental service><env Antigens><env Gene Products><env Polyproteins><env Protein><extracellular><host response><immunoresponse><innovate><innovation><innovative><integrin bound><lymph cell><mouse model><murine model><novel><oral cavity epithelium><oral epithelia><oral epithelium><parent grant><particle><pathophysiology><plasmalemma><prevent><preventing><receptor><receptor binding><receptor bound><recruit><social role><thymus derived lymphocyte><tissue degeneration><translation strategy><translational approach><translational strategy><transmission process>