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Metabolic imprinting of dendritic cell fate and function in tissues

Award Number: R01AI048638
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: 03/01/2001
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Metabolic imprinting of dendritic cell fate and function in tissues - ABSTRACT Dendritic cells (DCs) play a central role in sensing pathogens and tuning immune responses. Functionally distinct subsets of DCs can stimulate different types of immune responses, but DCs also display functional plasticity in response to microbial stimuli or signals from the tissue microenvironment. However, it is now clear that DCs sense not just microbial stimuli, but also various stress signals (e.g. amino acid starvation), through ancient stress sensing mechanisms, leading to a metabolic reprogramming of their function. In particular our recent work has revealed fundamental roles for two major amino acid sensors GCN2 and mTOR, in programming DCs to modulate adaptive immunity and inflammation. We have shown that GCN2 plays a role in programming DCs to respond to viral vaccination, and in controlling intestinal inflammation by promoting autophagy and suppressing inflammasome activation in gut APCs and epithelial cells. Furthermore, our recent data demonstrates that GCN2 regulates allergic inflammation in the lung. In addition to these effects of GCN2, we have recently shown that mTOR regulates developmental fate of DCs and alveolar macrophages (AMs) in the lung, and reprograms their metabolic state to modulate the outcome of allergic inflammation. In the following aims, we will determine the mechanisms of this metabolic imprinting. Aim 1: To determine the mechanisms by which mTOR controls the homeostasis and function of lung DCs and AMs in the steady state and during allergic inflammation. Our recent work demonstrates that in mice in which mTOR is genetically ablated in CD11c+ cells (mTORAPC mice): (i) CD103+ DCs and AMs in the lung are greatly reduced in number, in the steady state. (ii) Although the lung CD11c+CD11b+ DCs were numerically unaffected, they were skewed in their transcriptional identity towards the macrophage/monocytic profile. (iii) Lung allergic Th2 inflammation was skewed toward the Th17/neutrophilic phenotype. In the present aim, we will investigate the mechanisms underlying these effects, and investigate the potential role of 4E-BP3 dependent translational control, lipid metabolism and epigenetic reprograming in mediating the effects of mTOR signaling. Aim 2: To determine the mechanisms by which GCN2 regulates Th2 responses and allergic inflammation. Our preliminary data demonstrate that GCN2 knockout mice display markedly reduced allergic inflammation in the lung. In this aim we will determine the molecular mechanisms underlying this effect. The successful completion of these aims will yield rich mechanistic insights about metabolic imprinting of DC fate and 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 = $485,664 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	002	24	5/24/2024	NON-COMPETING CONTINUATION	$36,737
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	24	2/15/2024	NON-COMPETING CONTINUATION	$330,652
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	24	2/21/2024	SUPPLEMENT FOR EXPANSION	$118,275
														Subtotal = $485,664

Issue Date FY: 2023 ( Subtotal = $485,664 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	23	1/13/2023	NON-COMPETING CONTINUATION	$367,389
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	23	2/9/2023	SUPPLEMENT FOR EXPANSION	$118,275
														Subtotal = $485,664

Issue Date FY: 2022 ( Subtotal = $485,664 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	22	3/23/2022	SUPPLEMENT FOR EXPANSION	$118,275
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	22	3/21/2022	NON-COMPETING CONTINUATION	$367,389
														Subtotal = $485,664

Issue Date FY: 2021 ( Subtotal = $485,664 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	21	1/21/2021	NON-COMPETING CONTINUATION	$485,664
														Subtotal = $485,664

Issue Date FY: 2020 ( Subtotal = $485,665 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	001	20	4/22/2020	COMPETING CONTINUATION	$1
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Allergy and Infectious Diseases Research	000	20	1/30/2020	COMPETING CONTINUATION	$485,664
														Subtotal = $485,665

Issue Date FY: 2007 ( Subtotal = $320,485 )
2007	2007	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	8	2/26/2007	NON-COMPETING CONTINUATION	$320,485
														Subtotal = $320,485

Issue Date FY: 2006 ( Subtotal = $330,057 )
2006	2006	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	7	2/22/2006	NON-COMPETING CONTINUATION	$330,057
														Subtotal = $330,057

Issue Date FY: 2005 ( Subtotal = $338,000 )
2005	2005	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	6	2/17/2005	NON-COMPETING CONTINUATION	$338,000
														Subtotal = $338,000

Issue Date FY: 2004 ( Subtotal = $338,000 )
2004	2004	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	5	2/25/2004	COMPETING CONTINUATION	$338,000
														Subtotal = $338,000

Issue Date FY: 2003 ( Subtotal = $240,000 )
2003	2003	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	4		NON-COMPETING CONTINUATION	$240,000
														Subtotal = $240,000

Issue Date FY: 2002 ( Subtotal = $240,000 )
2002	2002	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Allergy and Infectious Diseases Research	000	3	4/19/2002	NON-COMPETING CONTINUATION	$240,000
														Subtotal = $240,000

Issue Date FY: 2001 ( Subtotal = $226,500 )
2001	2001	BAYLOR RESEARCH FOUNDATION	3600 GASTON AVENUE	DALLAS	TX	75246	DALLAS	USA	Allergy and Infectious Diseases Research	000	1	3/27/2001	NEW	$226,500
														Subtotal = $226,500

Grand Total All Awards = $4,461,363

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Metabolic imprinting of dendritic cell fate and function in tissues

Award Number: R01AI048638

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: 03/01/2001

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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