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Estrogen-mediated immune regulation in human and experimental inflammatory bowel disease

Award Number: R01DK128143
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Estrogen-mediated immune regulation in human and experimental inflammatory bowel disease - Project Summary/Abstract Regulatory T cell (Treg) immunosuppression is critical for maintaining immune tolerance to a diverse array of potential antigens in the intestinal mucosa. In patients with inflammatory bowel disease (IBD), chronic intestinal inflammation overwhelms local Treg function, allowing inflammation to persist. Our previous work and that of others have identified important roles for 17β-estradiol (estrogen, E2) signaling in promoting Treg differentiation and function. E2 signals through two nuclear receptors, alpha and beta (ERα, ERβ), to modulate gene transcription in target cells. Although they share high sequence homology, ERα and ERβ mediate distinct and often opposing functions on gene regulation. In previously published work, we showed that shifting the balance of E2 signaling towards ERα is generally pro-inflammatory, whereas shifting towards ERβ is generally protective. In recent preliminary studies using IBD patient samples, we observed significantly diminished ERβ expression in intestinal biopsy tissues and peripheral T cells from females with active Crohn’s disease (CD). We also found that ERβ-deficient T cells are resistant to ex vivo, TGFβ-dependent Treg differentiation, and that deletion of ERβ in a spontaneous ileitis model (SAMP/YitFC, “SAMP” mice) results in significant impairment of Treg transcriptional and functional responses, contributing to exacerbated inflammation. Therefore, the goal of this project is to determine the molecular and cellular mechanism(s) by which altered E2 signaling impacts Treg differentiation and function, contributing to intestinal inflammation. The mechanisms by which E2 signaling cross-talks with inflammatory signals to influence immune cell function are poorly understood. This proposal seeks to address this knowledge gap through our central hypothesis that dysregulated E2 signaling contributes to Treg transcriptional remodeling and loss-of-function, facilitating sustained intestinal inflammation in IBD. In Aim 1, we propose to delineate the molecular mechanisms by which ERα- and ERβ cross-talk with signaling downstream of TGFβ in primary T cells, influencing TGFβ-dependent Foxp3 expression and function. Aim 2 will determine the functional impact of rebalancing Treg-specific E2 signaling on intestinal inflammation in vivo, testing our hypothesis that augmenting Treg-specific ERβ signaling may prevent and/or rescue intestinal inflammation. Experiments will include adoptive transfer of ERβ-expressing Tregs to SAMP mice, as well as in vivo assays using a T cell-dependent colitis model. In Aim 3, we plan to determine the transcriptional and functional effects of rebalancing E2 signaling in CD patient Tregs using novel MaxCyte transfection technology, assessing ERα- and ERβ-specific effects on (i) TGFβ-dependent Foxp3 induction in naïve T cells and (ii) ex vivo suppressive function of Tregs. Successful completion of our proposed Aims will provide key mechanistic insight into the functional impact of E2 signaling in Tregs, an under-studied area with broad applicability to numerous diseases exhibiting dysregulation of ER expression and/or activation and subsequent reductions in Treg function.


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 = $355,097 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	$355,097
														Subtotal = $355,097

Issue Date FY: 2024 ( Subtotal = $476,447 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/14/2024	NON-COMPETING CONTINUATION	$387,804
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/18/2024	SUPPLEMENT FOR EXPANSION	$56,511
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	5/20/2024	NON-COMPETING CONTINUATION	$25,853
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	4	5/21/2024	SUPPLEMENT FOR EXPANSION	$6,279
														Subtotal = $476,447

Issue Date FY: 2023 ( Subtotal = $489,543 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/28/2023	SUPPLEMENT FOR EXPANSION	$31,395
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/3/2023	NON-COMPETING CONTINUATION	$458,148
														Subtotal = $489,543

Issue Date FY: 2022 ( Subtotal = $457,578 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/25/2022	NON-COMPETING CONTINUATION	$45,759
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/16/2022	NON-COMPETING CONTINUATION	$411,819
														Subtotal = $457,578

Issue Date FY: 2021 ( Subtotal = $419,771 )
2021	2021	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/17/2021	NEW	$419,771
														Subtotal = $419,771

Grand Total All Awards = $2,198,436

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Estrogen-mediated immune regulation in human and experimental inflammatory bowel disease

Award Number: R01DK128143

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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