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Bone Morphogenic Protein Receptor 1a signaling controls stability of Treg cell phenotype

Award Number: R21AI178316
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: 07/21/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Bone Morphogenic Protein Receptor 1a signaling controls stability of Treg cell phenotype - Abstract Despite extensive studies, environmental cues and signaling circuits regulating onset of autoimmune diseases are not completely understood. Here we report that a receptor of the TGF-β cytokine family, Bone Morphogenetic Protein Receptor 1α (BMPR1α, Alk-3) has important immunoregulatory functions. BMPR1α is upregulated by activated effector and Foxp3+ regulatory CD4+ T cells (TR cells) and modulates functions of both of these cell types. BMPR1α regulates inflammation by inhibiting generation of Th17 cells and sustaining TR cells. Abrogation of BMPR1α signaling in TR cells resulted in a gradual loss of Foxp3 expression and upregulation of transcription factors and cytokines specific for Th effector lineage including Rorgt, Batf, Hif1a, IL-17 and IFN-g. This data suggests that BMPR1α controls phenotypic stability of TR cells and regulates Th17/TR balance, critical for maintenance of peripheral tolerance and protection from autoimmune diseases. Cells which downregulate Foxp3 convert into effector Th cells (exTR cells) which produce proinflammatory cytokines and contribute to disease pathology in a number of autoimmune diseases. A recent RNA-seq transcriptome analyses of BMPR1α-deficient TR cells in situ showed upregulation of a number of epigenetic modifiers and transcription factors specific for effector Th cells including Med14, Supt16H, Setbp1, Tbx21 (Tbet) and Maf. These new data demonstrate that BMPR1α-deficient TR cells in unmanipulated mice are predisposed to follow epigenetic and transcription programme to dedifferentiate to exTR cells when subject to antigenic stimulation and inflammation. To gain mechanistic insight on the immunoregulatory role of BMPR1α we will combine ATAC-seq and RNA- seq analyses of epigenetic profile and transcriptomes to identify molecules involved in TR/exTR transition. We will test if TR/exTR transition can be regulated by pharmacological modulation of BMPR1α dependent signaling pathways. We have found that at the molecular level BMPR1a deficiency in TR cells led to upregulation of Kdm6b (Jmjd3) demethylase, an antagonist of polycomb repressive complex 2 (PRC2). We will examine if phenotype of BMPR1a deficient TR cells could be sustained by Kdm6b inhibitor. We will also generate mouse models to test additional compounds for their ability to impact BMPR1a signaling and modulate TR cell stability. In summary, proposed research will contribute to our understanding of immunoregulation and has the potential to outline new therapeutic strategies for inflammatory and autoimmune diseases.


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 = $0 )
2025	2024	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	2	4/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $200,569 )
2024	2024	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	2	6/18/2024	NON-COMPETING CONTINUATION	$200,569
														Subtotal = $200,569

Issue Date FY: 2023 ( Subtotal = $247,989 )
2023	2023	OLD DOMINION UNIVERSITY	HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	1	7/21/2023	NEW	$247,989
														Subtotal = $247,989

Grand Total All Awards = $448,558

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Bone Morphogenic Protein Receptor 1a signaling controls stability of Treg cell phenotype

Award Number: R21AI178316

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: 07/21/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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