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Ligand and transcriptional regulation of the nuclear receptor RORa on TH17 cell development and inflammation

Award Number: R01DK136298
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Ligand and transcriptional regulation of the nuclear receptor RORa on TH17 cell development and inflammation - SUMMARY The goal of our studies is to understand RORα’s role in the transcriptional regulation of TH17 cell pathogenicity and chronic inflammation. RORα is a member of the ligand-regulated nuclear receptor (NR) superfamily of transcription factors. Significantly less is known about RORα in the transcriptional regulation of TH17-mediated immunity. We and others recently published RORα is required for full TH17-cell development, particularly in mouse models of chronic inflammation. Despite this evidence, RORα is considered functionally redundant to RORγt, the lineage defining transcription factor of TH17 cells. As ligand-regulated transcription factors, NRs evolved to respond to endogenous small molecules, translating these signals into changes in gene expression. Synthetic small molecules can also be utilized to understand receptor function. Our data suggests that RORα/ligand-regulation may protect from chronic inflammation, including colitis. Given the evidence that both intra- and extra- cellular ligands regulate NR activity in TH17 cells, defining RORα and ligand mechanisms of action is key to understanding signaling pathways underlying homeostasis vs. pathogenesis. Therefore, understanding these processes may be essential to understand how RORα contributes to TH17 cells and disease. Our overarching goals are to elucidate the mechanisms that regulate RORα’s transcriptional activity and interacting partners, thus driving functionality in TH17 cells during inflammatory processes. Understanding RORα’s transcriptional role in TH17 cells may reveal a novel therapeutic option for the treatment of TH17-mediated chronic inflammatory disorders. We will achieve our goals by: 1) establishing how RORα transcriptionally promotes and maintains pathogenic TH17- mediated inflammation and 2) using pharmacological approaches to understand how ligands affect the transcriptional activity of RORα in TH17 cells. Collectively, our studies will uncover important transcriptional roles for RORα in TH17 cell biology and reveal whether targeting RORα may be advantageous for the treatment of TH17-mediated chronic inflammation.


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 = $618,072 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	6/11/2025	NON-COMPETING CONTINUATION	$61,806
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/20/2025	NON-COMPETING CONTINUATION	$556,266
														Subtotal = $618,072

Issue Date FY: 2024 ( Subtotal = $618,072 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/20/2024	NEW	$618,072
														Subtotal = $618,072

Grand Total All Awards = $1,236,144

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Ligand and transcriptional regulation of the nuclear receptor RORa on TH17 cell development and inflammation

Award Number: R01DK136298

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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