# Intermittent fasting restores salivary gland function in Sjögren’s syndrome

> **NIH NIH R01** · ADA FORSYTH INSTITUTE, INC. · 2021 · $472,625

## Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease affecting millions of Americans, in which
salivary glands are the primary target of autoreactive T cells, leading to hyposalivation, the major
disease hallmark. Hyposalivation (dry mouth) causes a variety of oral health issues and severely
compromises quality of life. SS has no cure and current treatments are predominantly palliative. Failure
of therapies for SS are inextricably linked to the inability to control autoinflammation; thus, we propose
to investigate both simultaneously. To achieve sustainable salivary secretion, development of
approaches to simultaneously enhance endogenous salivary gland regeneration and protect the glands
from further injury from autoimmune inflammation are critically needed. Our preliminary studies
strongly suggest that there are protective actions provided by intermittent fasting (IF) in SS. In non-
obese diabetic (NOD) mice, a well-defined spontaneous model of SS, IF enhances the proliferation of
salivary gland stem cells, and upregulates Wnt and Notch signaling and Peroxisome Proliferator-
Activated Receptor-driven fatty acid oxidation, which are critically involved in the expansion and
differentiation of multiple stem cell types. It also mitigates autoreactive T helper 1, T helper 17 and
cytotoxic T cell responses in the salivary gland-draining lymph nodes. The objective of this proposed
project is to determine the previously unexplored impact of IF on the activity of endogenous salivary
gland stem/progenitor cells and autoimmune inflammation in SS to unravel the underlying molecular
and cellular mechanisms of IF benefits, with the long-term goal of developing effective and targeted
therapies to fundamentally improve salivary gland function. Based on the literature and our preliminary
results, we formulated the central hypothesis that IF exerts beneficial actions on salivary gland
restoration through promoting endogenous salivary gland regeneration and diminishing T cell mediated
autoimmune inflammation in SS. This hypothesis will be tested through the following specific aims: In
Aim 1, we will dissect the potential molecular mechanisms for the impact of IF on the proliferation and
differentiation of salivary gland stem cells in the NOD mouse, a spontaneous model of SS; In Aim 2,
we will assess the impact of IF on the self-expansion and cellular plasticity of ductal salivary gland
progenitor cells and acinar cells, the function and plasticity of T cell subsets, and the attenuation of
autoimmune inflammation in the salivary tissues, using lineage tracing mouse models and an inducible
model of SS. Successful completion of this study will provide new targets for the development of
effective new therapeutics for SS-like exocrinopathy, as well as provide insight into the treatment of
xerostomia caused by radiation, medications or aging, and other autoimmune diseases that share
similarities in their pathogenesis with SS.

## Key facts

- **NIH application ID:** 10213312
- **Project number:** 1R01DE030646-01
- **Recipient organization:** ADA FORSYTH INSTITUTE, INC.
- **Principal Investigator:** Jing Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $472,625
- **Award type:** 1
- **Project period:** 2021-03-03 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10213312

## Citation

> US National Institutes of Health, RePORTER application 10213312, Intermittent fasting restores salivary gland function in Sjögren’s syndrome (1R01DE030646-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10213312. Licensed CC0.

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