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Mechanisms of mucosal autoinflammation elucidated by a novel monogenic transcription factor defect

Award Number: R01AI150913
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: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Mechanisms of mucosal autoinflammation elucidated by a novel monogenic transcription factor defect - Project Summary Discovery of the genetic basis of inborn errors of immunity in humans provides impactful information about genes, proteins, and pathways that are fundamentally important for healthy immune function. Inflammation is a critical component of immune activation that normally signals the presence of microbes to initiate molecular and cellular responses required to contain and eliminate a pathogen. However, aberrantly high inflammation is detrimental to host fitness and contributes to pathology in an array of human diseases. In order to control inflammation, there are many intracellular and secreted anti-inflammatory proteins that are transcribed in a cell- type and context-dependent manner. A prime example is IL-10, which when defective in humans causes monogenic very early-onset IBD. However, there is relatively limited knowledge about transcription factors that act as master regulators of these inducible anti-inflammatory genes in humans. We have now discovered a new human inborn error of immunity caused by novel loss-of-function mutations in the ELF4 transcription factor gene that we hypothesize serves as a master regulator at the intersection of interferon, inflammasome, and Th17 biology. The three patients identified through our genomics program suffer from mucosal autoinflammation with IBD features, fever, and oral ulcers, and we have now generated powerful Elf4 knockout, point mutant, and floxed mouse models to advance our knowledge. Our preliminary data in ELF4-mutant human and mouse cells emphasize cell type-specific functions of this factor, with increased inflammatory responses in myeloid and T cells associated with failed anti-inflammatory gene expression programs. We will pursue two aims to illuminate how ELF4 functions as a cornerstone in the cross-regulation of interferon, inflammasome, and Th17 responses. Aim 1) Dissect molecular and biochemical effects of WT and mutant ELF4 in myeloid and Th17 cells. Aim 2) Define the roles of WT and mutant ELF4 in cellular and organismal inflammatory responses mediated by myeloid and Th17 cells. The results of these investigations will provide invaluable new insights with direct relevance for understanding the etiology and devising targeted therapy in this new human disorder and, by extension, more broadly in prevalent inflammatory 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 = $562,848 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	5	3/17/2025	NON-COMPETING CONTINUATION	$562,848
														Subtotal = $562,848

Issue Date FY: 2024 ( Subtotal = $575,021 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	001	4	4/4/2024	NON-COMPETING CONTINUATION	$575,021
2024	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	3	4/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $575,021

Issue Date FY: 2023 ( Subtotal = $596,064 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	3	3/30/2023	NON-COMPETING CONTINUATION	$596,064
														Subtotal = $596,064

Issue Date FY: 2022 ( Subtotal = $596,845 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	2	3/10/2022	NON-COMPETING CONTINUATION	$596,845
														Subtotal = $596,845

Issue Date FY: 2021 ( Subtotal = $571,333 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	4/15/2021	NEW	$571,333
														Subtotal = $571,333

Grand Total All Awards = $2,902,111

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Mechanisms of mucosal autoinflammation elucidated by a novel monogenic transcription factor defect

Award Number: R01AI150913

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: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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