# Novel Role for the P2Y2 Receptor in the Autoimmune Disease Sjogren's Syndrome

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $623,962

## Abstract

Summary
 Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry
mouth, oral bacterial infections, poor nutrition and other disorders associated with decreased saliva production.
Loss of saliva is symptomatic of Sjögren's syndrome (SS), an autoimmune disease associated with
lymphocytic infiltration of the salivary gland, autoantibody production and ultimately tissue degeneration. 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 including tissue fibrosis, secondary autoimmune diseases (e.g. lupus, rheumatoid arthritis) and the
development of lymphoma. A major focus of this proposal is to identify the functional relevance of “alarmones”
that are produced at the site of initial tissue damage and the cellular mechanisms whereby alarmones mobilize
the systemic immune system leading to chronic inflammation. Among possible alarmones that initiate
autoimmune disease in salivary glands, our laboratory has investigated the effect of localized release of
nucleotides, such as ATP, from damaged cells or tissues. 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 occurs through
P2Y2R activation in SS salivary glands, which increases localized chemokine/cytokine levels and attracts
peripheral lymphocyte infiltration across the vascular endothelium into salivary glands. Specific Aims will fully
investigate the cell-specific mechanisms that initiate chronic inflammation at the level of P2Y2 receptors in the
salivary gland of SS mouse models and test the potential of targeting the P2Y2R in SS mouse models to
prevent a systemic immune response. Specific Aim 1 will address the hypothesis that P2Y2R activation in B
and T cells promotes their infiltration and proliferation in salivary glands of SS mouse models thereby
contributing to salivary gland dysfunction. Specific Aim 2 will address the hypothesis that P2Y2R
upregulation in salivary epithelium and vascular endothelium contributes to the autoimmune phenotype in SS
mouse models. Specific Aim 3 will evaluate the hypothesis that pharmacological antagonism of P2Y2Rs in
vivo reduces chronic inflammation of the salivary glands in two distinct SS mouse models. Successful
completion of this project would expedite human studies to target modulation of the P2Y2R in SS to prevent
loss of salivary gland function.

## Key facts

- **NIH application ID:** 9969383
- **Project number:** 5R01DE007389-30
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** GARY Andrew WEISMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $623,962
- **Award type:** 5
- **Project period:** 1992-08-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969383

## Citation

> US National Institutes of Health, RePORTER application 9969383, Novel Role for the P2Y2 Receptor in the Autoimmune Disease Sjogren's Syndrome (5R01DE007389-30). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9969383. Licensed CC0.

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