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Molecular characterization of the role for metabolites in immune cell differentiation

Award Number: R56AI061061
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: 08/04/2021
PERIOD OF PERFORMANCE END DATE: 09/26/2022

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Molecular characterization of the role for metabolites in immune cell differentiation - Abstract The dynamic regulation of metabolic states plays an active role in cellular differentiation decisions, and this occurs throughout mammalian development. The conservation of these processes in different species, developmental settings, and immune cell types suggests metabolism influences common mechanistic events needed for differentiation decisions in diverse cellular backgrounds. However, the interpretation of these conserved mechanisms must have a component of cell-type specificity to properly regulate the genome to promote appropriate differentiation in individual cellular settings. Therefore, it is important to define the conserved and cell-type specific mechanistic principles to understand how dietary and metabolic interventions influence immune cell differentiation in the context of healthy and disease states. In the previous funding cycle of this grant, we identified a role for alpha-ketoglutarate (αKG) in regulating the IL-2-sensitive gene program in T cells. Mechanistically, αKG-sensitive events enhanced the association of CTCF with a subset of sites in CD4+ T cells, and together with studies in cancer cells, the data indicated this overall activity is conserved in diverse cell-types. The data also suggested these events are interpreted in a cell-type specific manner, potentially based on the enhancer landscape of the cell. In this grant, we will extend these findings to address how αKG-sensitive CTCF sites are selected, and whether there are any cell-type dependent mechanisms selecting these sites. We will also define whether downstream mechanisms, such as enhancer activity, have sensitivity to metabolic states. In this context, we will address whether the enhancer landscape is regulated by short chain fatty acids such as butyrate and acetate. We will also define which aspects of metabolite-sensitive mechanisms are conserved between species, and how variation between the mouse and human genome influences the interpretation of conserved and cell-type specific events. Information gained in these studies will be critical for predicting the role for metabolic and dietary interventions in the treatment of immunological diseases or in promoting effective immune responses to infectious 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: 2023 ( Subtotal = -$320,786 )
2023	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	17	9/19/2023	COMPETING CONTINUATION	-$320,786
														Subtotal = -$320,786

Issue Date FY: 2022 ( Subtotal = $255,391 )
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	17	9/27/2022	COMPETING CONTINUATION	$0
2022	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	17	1/10/2022	COMPETING CONTINUATION	$255,391
														Subtotal = $255,391

Issue Date FY: 2021 ( Subtotal = $320,683 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	17	8/4/2021	COMPETING CONTINUATION	$320,683
														Subtotal = $320,683

Issue Date FY: 2010 ( Subtotal = $0 )
2010	2009	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	2/8/2010	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $351,000 )
2009	2009	UNIVERSITY OF WASHINGTON	3917 UNIVERSITY WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	9/17/2009	COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Grand Total All Awards = $606,287

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Molecular characterization of the role for metabolites in immune cell differentiation

Award Number: R56AI061061

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: 08/04/2021

PERIOD OF PERFORMANCE END DATE: 09/26/2022

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