Thursday, November 21, 2024 11/21/2024

Elucidating the molecular mechanisms underlying ligand-dependent REV-ERB activity in Th17 cells

Award Number: F31DK127643
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary/Abstract Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis are characterized by an inappropriate immune response to commensal gut flora that causes chronic damage to the gastrointestinal (GI) tract. Genome-wide association studies showing genes associated with T helper 17 (Th17) immune responses are strongly implicated in IBD susceptibility together with clinical evidence of Th17 cells in GI tissues of IBD patients have identified a central role for Th17 cells in IBD pathogenesis. Although Th17 cells are characterized by the production of IL-17A, they also produce many other molecules each with critical roles in regulating the immune response. This could explain why IL-17A-neutralizing antibodies have had little success in treating IBD, while targeting factors within Th17 cells that broadly regulate their expression of effector molecules may be a more effective strategy. To this end, we recently demonstrated that the closely related REV-ERB (REV-ERBa and REV-ERBb) nuclear receptors (NRs) are cell-intrinsic repressors of Th17 cell pathogenicity. Transcriptional repression of signature Th17 cell genes by the REV-ERBs is essential for limiting disease severity in mouse models of chronic inflammatory disease and treatment with synthetic REV-ERB ligands developed at Scripps Florida enhanced the protective effect. The porphyrin, heme, is the endogenous ligand for the REV-ERBs and my preliminary data indicate that heme is important for REV-ERB activity in Th17 cells. Since NR ligands evolved to transmit extracellular or intracellular signals into changes in gene expression, understanding the source and effects of heme-dependent REV-ERB activity in Th17 cells may reveal signaling pathways underlying IBD pathogenesis that could be exploited for therapeutic benefit. At the same time, although the basis for ligand- dependent NR activity is in their regulation of NR structure, contradictory evidence between published cell-based and structural studies has prevented understanding of the molecular basis for heme-dependent REV-ERB activity. My preliminary data reveal a potential solution to this conflict. My overarching hypothesis is that heme produced intracellularly in Th17 cells enhances REV-ERB repression of a pathogenic Th17 cell phenotype by stabilizing the REV-ERBs’ interaction with a transcriptionally repressive coregulator (corepressor) protein. I will test this hypothesis through two central aims: 1) I will identify the role of heme as a REV-ERB-dependent signaling molecule in Th17 cells and 2) I will define the heme-dependent structural changes that influence REV-ERB activity. I expect the results of these aims to characterize an underexplored signaling pathway in Th17 cells that could be targeted to treat IBD. In the process, I will receive comprehensive training in immunology and structural biology approaches from a unique, interdisciplinary mentorship team. Together with the extensive professional development resources at Scripps Florida, this team will ensure that I progress toward achieving my long-term goal of directing a research lab studying the molecular basis of chronic inflammatory diseases such as IBD.


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: 2024 ( Subtotal = -$3,000 )
2024	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	10/31/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3,000
														Subtotal = -$3,000

Issue Date FY: 2023 ( Subtotal = -$3,875 )
2023	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/15/2023	NON-COMPETING CONTINUATION	-$3,875
														Subtotal = -$3,875

Issue Date FY: 2022 ( Subtotal = $33,753 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	3/24/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$23,929
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	3/24/2022	NON-COMPETING CONTINUATION	-$23,929
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	4/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$717
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/7/2021	NON-COMPETING CONTINUATION	$33,036
														Subtotal = $33,753

Issue Date FY: 2021 ( Subtotal = $33,036 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	12/10/2020	NEW	$0
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	2/8/2021	NEW	$516
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/10/2020	NEW	$32,520
														Subtotal = $33,036

Grand Total All Awards = $59,914

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Elucidating the molecular mechanisms underlying ligand-dependent REV-ERB activity in Th17 cells

Award Number: F31DK127643

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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