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Regulation of colon epithelial repair by TNFR-dependent mechanisms

Award Number: R01DK148982
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: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Regulation of colon epithelial repair by TNFR-dependent mechanisms - PROJECT SUMMARY Tumor necrosis factor inhibitors are the most widely used biologic therapy for inflammatory bowel disease (IBD) - Crohn’s disease (CD) and ulcerative colitis. While most patients initially respond to treatment, the majority fail to achieve sustained mucosal healing or show disease progression. Interestingly, genome-wide association and candidate-allele studies for Crohn’s disease and ulcerative colitis identify both TNF receptors (TNFR1/tnfrsf1a) and (TNFR2/tnfrsf1b) as risk alleles for developing disease. Furthermore, single-nucleotide polymorphisms (SNPs) associated with anti-TNF non-response show over-representation of reduced TNFR2 expression. Preclinical work from our group showed that TNF signaling through either TNFR1 or TNFR2 is protective from development and severity of colitis. Boolean mathematical modeling from human clinical trials supports the rationale for defining the tissue-specific roles of the respective receptors in contributing to anti- TNF nonresponse and identification of novel therapeutic approaches to these targets. The goal of this proposal is to address key scientific barriers to clinical translation of these findings. Our hypothesis is that TNFRs mediate distinct protective functions in the context of colonic injury and inflammation. The Specific Aims of this proposal will address our hypothesis at multiple levels. Aim 1 will advance basic understanding of colonic subepithelial fibroblast populations that support crypt epithelial cell homeostasis and renewal. Our compelling preliminary data and published preclinical and human studies point to regulation of this process by TNFR1 expressed on distinct subsets of mesenchymal cells, including platelet-derived growth factor receptor alpha expressing (PDGFRA+) cells. We will explore how mesenchymal TNFR1 signaling regulates epithelial regeneration and integrin alpha 6-expressing (ITGA6+) fibroblast populations and potential approaches to restore regenerative fibroblast function. In Aim 2 we will address the therapeutic potential of selective activation of TNFR2 in translational models of colonic IBD. Our preliminary and published findings, and reports by other laboratories, support activation of TNFR2 as a novel therapeutic target to enhance mucosal healing, ulcer repair, and restoration of homeostatic intestinal epithelium in colitis. These studies will investigate TNFR2 activation in preclinical models of acute injury and chronic inflammation, define the impact of TNFR2 expressing cells - using a novel reporter mouse we developed for these studies - to define unique transcriptional populations in repair, and model TNFR2 agonism in human-derived colonoids from healthy controls, and responder, non-responder populations treated with anti-TNF. Thus, these studies will reveal important cellular and molecular mechanisms underlying the pathophysiology of IBD, with a focus on the impact of disruption of TNF signaling on the failure of mucosal healing in the colon.


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 = $827,905 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/15/2026	NEW	$827,905
														Subtotal = $827,905

Grand Total All Awards = $827,905

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Regulation of colon epithelial repair by TNFR-dependent mechanisms

Award Number: R01DK148982

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: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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