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Molecular Mechanisms of ROR-gamma-t Functional Regulation in Chromatin Environments

Award Number: R01AI196844
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Molecular Mechanisms of ROR-gamma-t Functional Regulation in Chromatin Environments - Abstract The transcription factor retinoic acid receptor-related orphan receptor γt (RORγt) is a master regulator of the adaptive immune response that plays foundational roles in shaping immunity, inflammation, and disease tolerance. RORγt supports thymopoesis and the rearrangement of T cell receptor loci in the adaptive immune system, the development of lymph node tissues, and serves as a ‘master transcription factor’ of pro-inflammatory IL-17 expressing T helper (Th17) cells. Dysregulation of RORγt function is associated with a variety of host autoimmune diseases, infection, hematological malignancies, and metabolic disorders. There have been extensive efforts to target RORγt for therapeutic purposes. Although there have been many clinical trials for RORγt chemical modulators, most have failed due to safety concerns. RORγt regulates transcription of target gene programs in Th17 cells by recruiting coregulatory proteins to specific DNA sequences in the genome called RORγt response elements (ROREs). Prior biochemical and structural studies have relied on reconstituting individual RORγt domains and small fragments of associated coregulatory proteins with/without ROREs to interrogate function. However, such studies have generally ignored the larger chromatin context – the native target of the RORγt-mediated transcriptional response – as a key regulatory factor of immunity. The fundamental hypothesis in this proposal is that the chromatin context, including both sequence and structure, directs the dynamic equilibrium that RORγt and coregulators enact during transcriptional regulation. The proposal builds upon foundational preliminary data, collaborative synergies, and interdisciplinary tools established in the investigators’ laboratories to interrogate RORγt biochemistry, structure, dynamics, and function on chromatin substrates to elucidate its role in transcriptional activation and immune response. Closely integrated with the in vitro work, an experimental autoimmune encephalomyelitis (EAE) mouse model for multiple sclerosis (MS) will be used to test key findings to assess how RORγt controls healthy vs. diseased states. In three Specific Aims, the multidisciplinary team of investigators will: (1) use high-resolution cryogenic electron microscopy (cryo-EM) to define the molecular architectures of chromatin-bound RORγt engaged with coregulatory assemblies; (2) employ solution phase hydrogen-deuterium exchange and crosslinking mass spectrometry measurements to interrogate the dynamic interplay between RORgt, coregulators, and native chromatin substrates, and how they change in response to ligands; (3) test and define the functional role of RORgt/coregulator/chromatin interactions in Th17 cells in vitro and in an EAE mouse model of MS. The results will establish a foundational understanding of RORγt structure and biology in its native chromatin environment and in the specific Th17 biological context. The work will have direct implications for developing novel avenues to design small molecule therapeutics that target this key immune modulator and its interactions in the broader chromatin context.


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 = $927,512 )
2026	2026	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	8/14/2026	NEW	$0
2026	2026	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	7/16/2026	NEW	$927,512
														Subtotal = $927,512

Grand Total All Awards = $927,512

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Molecular Mechanisms of ROR-gamma-t Functional Regulation in Chromatin Environments

Award Number: R01AI196844

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/16/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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