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Understanding the role of histone3 lysine4 trimethylation in neontal innate immune development under normal and inflammatory conditions

Award Number: R01AI141673
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT Neonates have dampened expression of pro-inflammatory cytokines and difficulty clearing pathogens, making them uniquely susceptible to infections. This is a worldwide health problem, with neonatal infections contributing to nearly one million deaths each year. The factors controlling neonatal specific immune responses and how and when they transition to more mature responses are poorly understood. Neonates rely heavily on innate immune responses to fight infections due to major defects in their adaptive immune system. Monocytes and macrophages are central to innate immune responses by sensing pathogens and initiating an inflammatory cascade that directs their clearance. Although both neonatal and adult monocytes/macrophages contain the same genetic code, they exhibit dramatic differences in pathogen-induced gene expression. Post- translational histone modifications can regulate gene transcription by influencing chromatin structure and accessibility, and likely play a role in this. Monocytes/macrophages demonstrate a developmental stage- specific increase in the H3K4 methyltransferase MLL1 with an associated gain in the activating histone modification histone 3 lysine 4 trimethylation (H3K4me3) at promoter sites of immunologically important genes as development progresses from extremely preterm neonate to adult. This gain allows for increasingly robust inflammatory responses as development advances. Microbial colonization of the skin and gastrointestinal tract occurs after birth and is associated with type 1 interferon expression, which is believed to guide immune system maturation and prevent detrimental pathogen responses. Chorioamnionitis is an inflammatory process affecting neonates around the time of birth, which negatively impacts immune system development and predisposes exposed neonates to long-term immune-related complications. The central hypothesis of this proposal is that neonatal monocytes/macrophages are largely un-patterned with H3K4me3 due to lack of in utero microbial exposure, and that postnatal microbial exposure stimulates low grade type 1 IFN expression which drives MLL1 expression and directs macrophage H3K4me3 deposition in a developmental stage-specific manner. Chorioamnionitis exposure stimulates a developmentally inappropriate level of type 1 interferon expression, which results in dysregulated MLL1 expression and global remodeling of the neonatal monocyte/macrophage landscape with subsequent dysfunctional monocyte/macrophage responses. This hypothesis will be investigated via the following specific aims: 1) Characterize normal human monocyte H3K4me3 patterning during infancy and early childhood and determine how developmental stage-specific H3K4me3 monocyte patterning impacts chromatin accessibility and gene expression, 2) Determine the requirement and sufficiency of type 1 interferons in MLL1-driven H3K4me3 placement in murine macrophage development and function, and 3) Determine the roles of type 1 interferons and MLL1 in chorioamnionitis-induced murine macrophage H3K4me3 remodeling and subsequent function.


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: 2024 ( Subtotal = $347,839 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	5	2/1/2024	NON-COMPETING CONTINUATION	$347,839
														Subtotal = $347,839

Issue Date FY: 2023 ( Subtotal = $386,273 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	4	1/17/2023	NON-COMPETING CONTINUATION	$386,273
														Subtotal = $386,273

Issue Date FY: 2022 ( Subtotal = $386,067 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	3	1/18/2022	NON-COMPETING CONTINUATION	$386,067
														Subtotal = $386,067

Issue Date FY: 2021 ( Subtotal = $388,865 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	001	2	4/15/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$388,865
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	003	2	9/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$345,360
2021	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	4/15/2021	NEW	$0
2021	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	002	1	9/14/2021	NEW	-$345,360
														Subtotal = $388,865

Issue Date FY: 2020 ( Subtotal = $400,162 )
2020	2020	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	2/7/2020	NEW	$400,162
														Subtotal = $400,162

Grand Total All Awards = $1,909,206

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Understanding the role of histone3 lysine4 trimethylation in neontal innate immune development under normal and inflammatory conditions

Award Number: R01AI141673

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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