R01DE029833

Targeting P2 receptors to restore salivary and lacrimal gland function in Sjogren's syndrome - Summary.

Sjögren’s syndrome (SS), an autoimmune exocrinopathy of the salivary and lacrimal glands, affects ~ 4 million Americans, 90% of whom are women. SS is characterized by sialadenitis and dacryoadenitis, decreased saliva (i.e., xerostomia) and tear production (i.e., xerophthalmia) and the presence in blood serum of autoantibodies against Ro/SSA and La/SSB.

Xerostomia and xerophthalmia in SS patients can lead to periodontitis, yeast and bacterial infections, digestive disorders, and vision deterioration that severely reduce the quality of life for patients. Ultimately, chronic inflammation in SS leads to secondary autoimmune diseases, tissue fibrosis, and lymphoma.

Therapy for SS is limited to symptom management through external hydration, artificial saliva and tears, and muscarinic receptor agonists that induce fluid secretion from residual exocrine acinar cells. Such remedies are universally judged to be inadequate and thus, development of more effective SS treatments is essential.

Our research focuses on cell surface P2X7 and P2Y2 receptors for extracellular ATP, the intracellular chemical form of energy that when released from damaged salivary glands initiate inflammatory responses. Our studies show that P2X7R and P2Y2R antagonists enhance saliva secretion and reduce lymphocytic foci in salivary glands of two different mouse models of SS. Antagonism of the P2X7R also reduces lymphocytic accumulation in the lacrimal glands and increases tear secretion.

These antagonists have not been used to treat human SS, although P2X7R is upregulated in salivary glands of SS patients compared to non-SS controls. P2X7R activation in salivary glands also induces maturation and release of IL-1β, an SS-related cytokine that upregulates P2Y2R in immune and epithelial cells, suggesting that P2X7R and P2Y2R contribute together to SS development.

This project will investigate the ability of P2X7R and/or P2Y2R antagonists to increase saliva and/or tear secretion and reduce sialadenitis and/or dacryoadenitis in mouse models of SS. These findings will be validated by assessing P2X7R and P2Y2R expression in archived human SS and control minor salivary gland biopsies and evaluating effects of P2X7R and/or P2Y2R antagonism in freshly isolated human salivary and lacrimal gland cells.

Specific Aim 1 will investigate the hypothesis that P2X7R and P2Y2R play sequential roles in chronic sialadenitis and glandular dysfunction in SS mouse models and can be antagonized to treat SS in vivo.

Specific Aim 2 will investigate the hypothesis that P2X7R and P2Y2R activation in lacrimal gland epithelial cells promotes dry eye disease in mouse models of SS.

Specific Aim 3 will investigate P2X7R and P2Y2R-mediated proinflammatory responses in human primary salivary and lacrimal gland cells and human SS minor salivary gland biopsies.

Successful completion of this proposal will represent a critical step towards realization of the ultimate goal of targeting the P2X7R and/or P2Y2R to treat SS in humans.

University Of Missouri System

NIDCR EXTRAMURAL RESEARCH PROVIDES RESEARCH FUNDS TO SUPPORT BASIC, TRANSLATIONAL, AND CLINICAL RESEARCH IN DENTAL, ORAL, AND CRANIOFACIAL HEALTH AND DISEASE THROUGH GRANTS, COOPERATIVE AGREEMENTS, AND CONTRACTS THAT SUPPORT SCIENTISTS WORKING IN INSTITUTIONS THROUGHOUT THE UNITED STATES AND INTERNATIONALLY. EXTRAMURAL PROGRAMS PLAN, DEVELOP, AND MANAGE SCIENTIFIC PRIORITIES THROUGH PORTFOLIO ANALYSES AND CONSULTATION WITH STAKEHOLDERS, ENCOURAGING THE MOST PROMISING DISCOVERIES AND EMERGING TECHNOLOGIES FOR RAPID TRANSLATION TO CLINICAL APPLICATIONS. THE INTEGRATIVE BIOLOGY AND INFECTIOUS DISEASES PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH PROGRAMS ON ORAL MICROBIOLOGY, SALIVARY BIOLOGY AND IMMUNOLOGY, ORAL AND SALIVARY GLAND CANCERS, NEUROSCIENCE OF OROFACIAL PAIN AND TEMPOROMANDIBULAR DISORDERS, MINERALIZED TISSUE PHYSIOLOGY, DENTAL BIOMATERIALS, AND TISSUE ENGINEERING AND REGENERATIVE MEDICINE. THE BRANCH AIMS TO ACCELERATE PROGRESS IN BASIC AND TRANSLATIONAL RESEARCH IN THESE AREAS, AND FURTHER STIMULATE THE DISCOVERY PIPELINE BASED ON CLINICAL NEEDS. THE TRANSLATIONAL GENOMICS RESEARCH PROGRAMS SUPPORTS BASIC AND TRANSLATIONAL RESEARCH IN GENETICS, GENOMICS, DEVELOPMENTAL BIOLOGY, AND DATA SCIENCE TOWARD THE GOAL OF IMPROVING DENTAL, ORAL, AND CRANIOFACIAL HEALTH. THE FOCUS IS ON DECIPHERING THE GENETIC, MOLECULAR, AND CELLULAR MECHANISMS UNDERLYING DENTAL, ORAL, AND CRANIOFACIAL DEVELOPMENT AND ANOMALIES. THE BEHAVIORAL AND SOCIAL SCIENCES RESEARCH PROGRAMS SUPPORTS BASIC AND APPLIED RESEARCH TO PROMOTE ORAL HEALTH, TO PREVENT ORAL DISEASES AND RELATED DISABILITIES, AND TO IMPROVE MANAGEMENT OF CRANIOFACIAL CONDITIONS, DISORDERS, AND INJURY. THE PROGRAM PRIORITIZES MECHANISTIC RESEARCH THAT CONTRIBUTES TO A CUMULATIVE SCIENCE OF BEHAVIOR CHANGE, TO MAXIMIZE THE RIGOR, RELEVANCE, AND DISSEMINATION OF EFFICACIOUS BEHAVIOR CHANGE INTERVENTIONS. THE CLINICAL RESEARCH PROGRAMS SUPPORTS PATIENT-ORIENTED, POPULATION, AND COMMUNITY BASED RESEARCH AIMED AT IMPROVING THE DENTAL, ORAL, AND CRANIOFACIAL HEALTH OF THE NATION. THE CENTER FOCUSES ON A VARIETY OF DISEASES AND CONDITIONS THROUGH CLINICAL TRIALS, EPIDEMIOLOGIC STUDIES, PRACTICE-BASED RESEARCH, THE HIV/AIDS AND ORAL HEALTH PROGRAM, AND STUDIES OF ORAL HEALTH DISPARITIES AND INEQUITIES IN ALL AREAS OF NIDCR PROGRAMMATIC INTEREST. THE PROGRAM ENCOURAGES INVESTIGATIONS THAT HAVE THE POTENTIAL TO TRANSLATE FINDINGS INTO EVIDENCE-BASED CLINICAL APPLICATIONS. THE RESEARCH TRAINING AND CAREER DEVELOPMENT EXTRAMURAL PROGRAMS SPAN THE CAREER STAGES OF SCIENTISTS, SUPPORTING RESEARCH TRAINING AND CAREER DEVELOPMENT FOR PHD AND DUAL DEGREE DDS/DMD-PHD STUDENTS, POSTDOCTORAL SCHOLARS, AND EARLY CAREER, MIDCAREER, AND ESTABLISHED INVESTIGATORS. THE PROGRAMS MANAGE SUPPORT FOR FELLOWSHIPS, RESEARCH TRAINING GRANTS, CAREER DEVELOPMENT AND CAREER TRANSITION AWARDS, NIH LOAN REPAYMENT AWARDS, AND DIVERSITY SUPPLEMENTS TO SUPPORT RESEARCH EXPERIENCES FOR HIGH SCHOOL STUDENTS THROUGH INVESTIGATORS. NIDCR PARTICIPATES IN THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) AND SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAMS. THE SBIR PROGRAM IS INTENDED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.THE STTR PROGRAM IS INTENDED TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND DISORDERS AND IMPROVING THE ORAL HEALTH OF ALL AMERICANS. EXTRAMURAL PROGRAMS SUPPORT RESEARCH AND RESEARCH TRAINING TO ESTABLISH THE FOUNDATION FOR SCIENTIFIC DISCOVERIES THAT INCLUDE TRANSPARENT AND RIGOROUS PLANNING, PRIORITY SETTING, CONTINUOUS AND CONSISTENT REVIEWS OF PROGRESS, AND FOCUS ON THE DEVELOPMENT OF A DIVERSE, HIGHLY SKILLED, AND NIMBLE WORKFORCE THAT CAN RAPIDLY RESPOND TO SCIENTIFIC BREAKTHROUGHS AND PUBLIC HEALTH CHALLENGES. EXTRAMURAL PROGRAMS ARE ACCOUNTABLE FOR THE EFFICIENT AND EFFECTIVE USE OF TAXPAYER FUNDS TO SUPPORT RESEARCH ON DENTAL, ORAL, AND CRANIOFACIAL DISEASES AND EMPLOY EVALUATION DOMAINS, FROM NEEDS ASSESSMENT AND STRATEGIC PLANNING TO IMPLEMENTATION AND PROCESS EVALUATION, PERFORMANCE MEASUREMENT, AND OUTCOMES AND IMPACT ANALYSIS TO EVALUATE STRATEGIC OBJECTIVES

93.121 - Oral Diseases and Disorders Research

National Institute of Dental and Craniofacial Research (NIDCR) [HHS - NIH]

Columbia, Missouri 652114405 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 426% from $611,605 to $3,216,546.