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Trans-ancestry, single-cell multiomics dissection of IBD-associated loci in CD4 memory T cells

Award Number: R01DK138458
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: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Trans-ancestry, single-cell multiomics dissection of IBD-associated loci in CD4 memory T cells - PROJECT SUMMARY/ABSTRACT Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), affect ~3.7 million Americans and Europeans, and several hundred thousand more worldwide. Genome-wide association studies have identified more than 200 IBD loci, but distinguishing causal genetic variants from non-causal variants in linkage disequilibrium, and understanding how non-coding, presumably regulatory variants with the strongest association signals in most IBD loci confer risk are challenges for functional and clinical translation. Multiomic data integration and epigenetic fine mapping in IBD-relevant cell types and contexts can bridge knowledge gaps between statistical genetic associations and a better understanding of underlying pathogenic mechanisms. A prime example of a non-coding locus with multiple blocks of IBD-associated variants in linkage disequilibrium is the chromosome 5p13 locus ~250 kb from PTGER4 that is one of the most significant findings from genetic studies of IBD in both European and African American ancestry groups. PTGER4 encodes EP4, one of two major PGE2 receptors on T cells. PGE2, together with IL-1β and IL-23, which also have receptors encoded by IBD risk loci genes, are overexpressed in IBD tissues and modulate Th17 immune cell development and plasticity. Non-steroidal anti-inflammatory drugs inhibit prostaglandin synthesis and may cause flares of IBD, possibly due to disruption of normal immune regulation. The aforementioned rationale motivated us to perform single-cell trimodal omics assays for transposase accessible chromatin (ATAC), gene expression, and cell surface protein epitope expression in paired T cell samples from healthy young adults that were exposed in ex vivo experiments to activation stimuli, IL-1β and IL-23, with or without PGE2. Our pilot study shows a significant enrichment of IBD-associated variants in T cell subtype-specific, especially CD4 memory T cell subtype-specific, ATAC peaks and significant inhibition of T cell activation by PGE2 in multiple T cell subtypes. We hypothesize that IBD-associated genetic variants interfere with normal inhibitory effects of PGE2 on T cell activation in specific CD4 memory T cell subtypes that are also exposed to activation stimuli, IL-1β and IL-23. We propose a trans- ancestry, single-cell trimodal omics approach to test our hypothesis. In Aim 1, we will perform large-scale, single- cell trimodal omics experiments in CD4 memory T cells from European and African American/West African ancestry study subjects and build a first-in-class single-cell trimodal omics atlas of CD4 memory T cells. In Aim 2, we will perform integrative and trans-ancestry analyses of single-cell trimodal omics and genetic data to dissect IBD-associated loci and to examine similarities and differences of regulatory networks between the two ancestry groups. We expect to identify the most probable non-coding IBD risk variants and their most probable gene targets in specific CD4 memory T cell subtypes exposed to activation stimuli, IL-1β, IL-23, and PGE2. Our project will complement ongoing research by NIDDK IBD Genetics Consortium investigators and will also be useful for the interpretation and prioritization of genetic variants for functional studies in other immune-mediated 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 = $476,998 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/4/2026	NON-COMPETING CONTINUATION	$476,998
														Subtotal = $476,998

Issue Date FY: 2025 ( Subtotal = $477,000 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	5/19/2025	NON-COMPETING CONTINUATION	$47,701
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$429,299
														Subtotal = $477,000

Issue Date FY: 2024 ( Subtotal = $477,000 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/16/2024	NEW	$477,000
														Subtotal = $477,000

Grand Total All Awards = $1,430,998

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Trans-ancestry, single-cell multiomics dissection of IBD-associated loci in CD4 memory T cells

Award Number: R01DK138458

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: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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