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Defining Sjögren’s pathogenesis by endotype: maladaptive responses of endogenous salivary gland mesenchymal stromal cells

Award Number: R01DE033396
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: 08/09/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Defining Sjögren’s pathogenesis by endotype: maladaptive responses of endogenous salivary gland mesenchymal stromal cells - Sjögren's disease (SjD), a common systemic autoimmune disease characterized by severe oral and ocular dryness and multi-organ involvement, has no disease modifying treatment available. Clinical trials to date have failed due to the clinical and biologic heterogeneity of SjD. As a result, it is important to subset SjD patients into pathobiologically similar groups, called endotypes. SjD patients who have a high number of lymphocytes in their salivary gland (SG) represent one endotype. This biopsy positive (Bx+) endotype has high cytokines that signal via Janus kinases (JAKs) and higher levels of autoantibodies. Another approach to generate biologically unique endotypes is to stratify by hallmark symptoms of dryness, pain, and fatigue. Mesenchymal stromal cells (MSCs) are enriched in SjD compared to control SGs and have divergent signaling pathways preclinically, suggesting that SG-MSCs might drive pathogenesis. The long-term goal is to mechanistically explain and generate therapies that target SG-MSCs in SjD. The overall objective of this application is to define how SjD endotypes modify MSC immunobiology, comparing mouse to human SG-MSCs. The central hypothesis is that MSCs are drivers of SjD pathogenesis through their maladaptive response to the cytokines unique to certain endotypes. The rationale for this project is based on new data that SG-MSCs treated with IFN become maladaptive and promote CD4+CXCR3+ T-cell and B-cell chemotaxis. These new data identify targetable maladaptive MSC behavior; however, the response to other inflammatory cytokines in endotype-specific SjD SG microenvironments is unknown. This knowledge is critical to define and target the pathogenic contributions of SG-MSCs in SjD. The central hypothesis will be tested by pursuing two specific aims: 1) determine the signaling pathways driving maladaptive mouse MSCs and SjD using multiple JAK inhibitors as translational immunopharmacological probes in Bx+ endotype; and 2) define pathologic responses and heterogeneity of human MSCs in SjD by endotype. In aim 1, Bx+ phenotype SjD mice will be treated with JAK inhibitors as immunopharmacological probes. SG-MSC transcript and protein profile, localization, and neighbors in situ will be determined using sequential FISH with hybridization chain reaction (seqFISH-HCR) by each treatment. SG-MSC maladaptive phenotype and function will be verified in vitro and SjD-like disease in mice will be measured. In aim 2, human MSC transcript and protein profiles, localization, and neighbors will be determined, comparing endotypes. Maladaptive MSC behavior will be mechanistically tested in vitro with aim 1 JAK inhibitors, identifying parallels between mice and humans. The proposed research is innovative, because it focuses on SjD endotypes, critical to guiding future pharmacologic MSC targeting and to deconvoluting SjD heterogeneity. Furthermore, it uses seqFISH-HCR technology for high resolution insight into the MSC phenotype in situ. The proposal is significant because it clarifies the pathobiology of a novel immunomodulatory cell, the SG-MSC, by SjD endotype, opening new horizons for MSC- and SjD endotype-targeted therapies. It also performs highly translatable comparisons in vivo between JAK inhibitors.


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: 2026 ( Subtotal = $686,512 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Oral Diseases and Disorders Research	001	3	7/9/2026	NON-COMPETING CONTINUATION	$0
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Oral Diseases and Disorders Research	000	3	5/25/2026	NON-COMPETING CONTINUATION	$686,512
														Subtotal = $686,512

Issue Date FY: 2025 ( Subtotal = $686,512 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Oral Diseases and Disorders Research	000	2	5/16/2025	NON-COMPETING CONTINUATION	$686,512
														Subtotal = $686,512

Issue Date FY: 2024 ( Subtotal = $700,387 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Oral Diseases and Disorders Research	000	1	8/8/2024	NEW	$700,387
														Subtotal = $700,387

Grand Total All Awards = $2,073,411

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Defining Sjögren’s pathogenesis by endotype: maladaptive responses of endogenous salivary gland mesenchymal stromal cells

Award Number: R01DE033396

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: 08/09/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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