NIH grant: Molecular Mechanisms of ROR-gamma-t Functional Regulation in Chromatin Environments (1R01AI196844-01A1)

retained text

NIH grant 1R01AI196844-01A1: Molecular Mechanisms of ROR-gamma-t Functional Regulation in Chromatin Environments
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Patrick Robert Griffin. Award: $927512.
Start: 2026-07-16T00:00:00.
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.

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