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Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis

Award Number: R01DE029472
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: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 06/09/2025

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Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis - Project Summary Sjögren’s syndrome (SS) is an autoimmune disease in which exocrine tissue is damaged, resulting in loss of tears and saliva. Primary SS (pSS) affects salivary and lacrimal tissue and results in many serious systemic disease manifestations. Once diagnosis is achieved, no SS-specific curative treatment options are available; rather treatments for SS are palliative. Thus, there is a critical need to identify etiologic events that will facilitate earlier diagnosis of SS and development of therapeutics that mitigate the progression of this debilitating disease. Studies in our laboratory revealed that Myeloid Differentiation Factor Primary Response Protein 88 (MyD88) is essential for pSS development. MyD88 is an adaptor molecule that is expressed ubiquitously and is required for most Toll-like receptor (TLR) and IL-1 receptor (IL-1R) family member signaling. Notably, TLRs and IL-1R family members are elevated locally (in salivary tissue) and in peripheral blood cells of SS patients, suggesting these receptors contribute to SS. Our central hypotheses are that (i) tissue-specific MyD88 expression dictates distinct pSS disease manifestations and that (ii) activation of MyD88-dependent signaling networks drives pSS pathogenesis. Our objectives are to identify the tissue-specific contributions of MyD88 and to determine the MyD88-mediated signaling networks that govern pSS disease pathogenesis. We will employ a pSS mouse model (NOD.B10) and a conditional knockout strain of NOD.B10 mice developed in our laboratory that lacks expression of MyD88 in the hematopoietic compartment (immune cells) specifically. These mice provide a unique model system to examine the role of MyD88 in pSS directly. The rationale for this proposal rests on the fact that activation of MyD88-mediated signaling pathways contributes to many autoimmune diseases. Both salivary tissue and immune cells express receptors that promote inflammation via MyD88, such as TLRs and IL-1R family members. Our studies in pSS mice deficient in MyD88 demonstrate that MyD88 is crucial for pSS pathogenesis; however, the specific cell types that express MyD88 in disease and the MyD88-dependent signaling pathways that are activated in pSS are incompletely understood. We will test our hypotheses by completion of three specific aims: (1) Identify immune cell-specific contributions of MyD88 to pSS pathogenesis, (2) Evaluate MyD88-dependent IL-36-related cytokines in pSS, and (3) Assess the role of the MyD88-dependent endosomal TLRs, TLR7 and TLR9, in pSS. This study is innovative because it will uncover new mechanisms related to the role of MyD88-dependent signaling networks in pSS and will identify specific cell types that mediate distinct pSS disease manifestations. Targeted blockade of MyD88-dependent TLR and IL-1R family member signaling pathways represents an innovative therapeutic approach for the treatment of pSS. This proposal is significant because it will reveal new mechanisms that govern chronic inflammation in pSS. Insights obtained from the proposed studies will reveal novel pathways that can be targeted to treat pSS and other autoimmune diseases.


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 = $0 )
2026	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	5	2/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $439,605 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	001	6	6/10/2025	COMPETING CONTINUATION	$439,605
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	5	6/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $439,605

Issue Date FY: 2024 ( Subtotal = $367,703 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	001	5	6/13/2024	NON-COMPETING CONTINUATION	$30,017
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	5	3/22/2024	NON-COMPETING CONTINUATION	$337,686
														Subtotal = $367,703

Issue Date FY: 2023 ( Subtotal = $371,743 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	4	3/28/2023	NON-COMPETING CONTINUATION	$371,743
														Subtotal = $371,743

Issue Date FY: 2022 ( Subtotal = $368,162 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	3	3/31/2022	NON-COMPETING CONTINUATION	$334,693
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	001	3	4/21/2022	NON-COMPETING CONTINUATION	$33,469
														Subtotal = $368,162

Issue Date FY: 2021 ( Subtotal = $372,018 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	2	3/3/2021	NON-COMPETING CONTINUATION	$372,018
														Subtotal = $372,018

Issue Date FY: 2020 ( Subtotal = $375,482 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Oral Diseases and Disorders Research	000	1	3/25/2020	NEW	$375,482
														Subtotal = $375,482

Grand Total All Awards = $2,294,713

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Analysis of MyD88-mediated immune activation in Sjogrens syndrome pathogenesis

Award Number: R01DE029472

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: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 06/09/2025

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