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Intermittent fasting restores salivary gland function in Sjögren’s syndrome

Award Number: R01DE030646
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/03/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Intermittent fasting restores salivary gland function in Sjögren’s syndrome - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $472,625 )
2025	2025	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	$425,363
2025	2025	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	5	5/7/2025	NON-COMPETING CONTINUATION	$47,262
														Subtotal = $472,625

Issue Date FY: 2024 ( Subtotal = $463,173 )
2024	2024	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	4	2/9/2024	NON-COMPETING CONTINUATION	$425,363
2024	2024	ADA FORSYTH INSTITUTE, INC.	245 1ST ST 17TH FLOOR	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	4	6/18/2024	NON-COMPETING CONTINUATION	$37,810
														Subtotal = $463,173

Issue Date FY: 2023 ( Subtotal = $472,625 )
2023	2023	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	3	2/17/2023	NON-COMPETING CONTINUATION	$472,625
														Subtotal = $472,625

Issue Date FY: 2022 ( Subtotal = $467,899 )
2022	2022	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	001	2	4/20/2022	NON-COMPETING CONTINUATION	$42,536
2022	2022	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	2	2/2/2022	NON-COMPETING CONTINUATION	$425,363
														Subtotal = $467,899

Issue Date FY: 2021 ( Subtotal = $472,625 )
2021	2021	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Oral Diseases and Disorders Research	000	1	3/3/2021	NEW	$472,625
														Subtotal = $472,625

Grand Total All Awards = $2,348,947

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Intermittent fasting restores salivary gland function in Sjögren’s syndrome

Award Number: R01DE030646

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/03/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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