Thursday, October 30, 2025 10/30/2025

Role of Sam68 in Proinflammatory Signaling

Award Number: R01DK128463
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Role of Sam68 in Proinflammatory Signaling - Abstract Ulcerative colitis (UC) is a chronic form of inflammatory bowel disease (IBD) with no cure. Current treatment strategies offer only partial remission, with many patients remaining refractory to treatment, and carry risks of significant adverse events including serious infections and cancer. Thus, an improved understanding of inflammatory signaling pathways and identification of novel preclinical mechanisms are critical challenges in IBD research. Signaling downstream of the proinflammatory cytokine tumor necrosis factor (TNF) and toll like receptor (TLR) pathways play major roles in IBD pathogenesis. In previous work, we discovered that the RNA binding protein Sam68 is required for both TNF- and TLR-induced activation of the transcription factor NF-κB, a master regulator of inflammation, suggesting that Sam68 contributes to NF-κB-dependent inflammation. Our new preliminary results show that Sam68 is prominently expressed in human and murine intestinal epithelial cells (IEC); Sam68 knockout (KO) mice are significantly protected from dextran sulfate sodium (DSS)- and oxazolone-induced colitis; and Sam68 protein is significantly elevated in inflamed colons of UC patients. Based on this, we hypothesize that Sam68 is a critical mediator of inflammation in IECs, and targeting IEC Sam68 will provide a novel therapeutic strategy in UC via dual inhibition of TNF- and TLR-mediated inflammatory pathways. We propose to study the molecular mechanisms of IEC-specific Sam68 signaling in human and experimental murine colitis using cutting edge tools such as 3D colonoids derived from UC patient colonocytes and novel IEC-specific Sam68 conditional KO (cKO) mice. Aim 1 will delineate molecular mechanisms of IEC-specific Sam68 signaling in TNF- and TLR-induced inflammatory signaling and identify the structural domains and posttranslational modifications of Sam68 required for its inflammatory functions. Aim 2 will study the in vivo role(s) of Sam68 in primary IECs under homeostatic and inflammatory conditions, using Sam68-cKO mice challenged with DSS and oxazolone as experimental colitis models, and using a spontaneous colitis model, Sam68-cKO / Wiscott Aldrich Syndrome Protein (WASP) KO double KO mice. This aim will utilize 3D colonoids prepared from wild type and Sam68-KO mice to study role of Sam68 in IEC proliferation, permeability and inflammatory signaling to study the homeostatic role of Sam68. Aim 3 will delineate the proinflammatory role of Sam68 in UC patients. This aim will study IEC-specific growth, proliferation, apoptosis, and expression of TJ proteins, and activation of proinflammatory signaling in IEC's and mucosal immune cells using co-culture assays of control and patient derived 3D intestinal organoids and immune cells. Successful completion of this study will fill critical knowledge gaps in understanding novel mechanisms underlying TNF- and TLR-dependent inflammatory signaling in UC and pave the way for the development of novel therapeutics targeting Sam68 to treat UC. Moreover, this study will also serve as the basis to explore the role of Sam68 in other TNF- and TLR-dependent chronic inflammatory diseases as well.


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 = $562,281 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/20/2025	NON-COMPETING CONTINUATION	$506,054
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	6/26/2025	NON-COMPETING CONTINUATION	$56,227
														Subtotal = $562,281

Issue Date FY: 2024 ( Subtotal = $543,870 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	5/3/2024	NON-COMPETING CONTINUATION	$543,870
														Subtotal = $543,870

Issue Date FY: 2023 ( Subtotal = $563,698 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/9/2023	NON-COMPETING CONTINUATION	$563,698
														Subtotal = $563,698

Issue Date FY: 2022 ( Subtotal = $565,115 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/29/2022	NEW	$565,115
														Subtotal = $565,115

Grand Total All Awards = $2,234,964

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Role of Sam68 in Proinflammatory Signaling

Award Number: R01DK128463

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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