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Metabolic perturbations in conventional dendritic cells modulate Tfh13 induction in asthmatic sensitization

Award Number: R01HL162991
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Allergic asthma is among the most common chronic lung diseases worldwide, and despite advances in treatment asthma prevalence continues to rise globally. Allergic asthma is largely driven by IgE antibodies that target environmental allergens. The production of allergen-specific IgE requires T follicular helper 13 cells (Tfh13) which must first be polarized by dendritic cells (DCs). However, a critical knowledge gap remains: how do DCs gain the ability to induce Tfh13s? By studying DC responses to allergic stimuli, we have determined that allergens induce a unique metabolic program in DCs, characterized by increased glutamine metabolism. We identified that allergen stimulated DCs exhibit aberrant TCA cycle metabolism, which leads to accumulation of α-ketoglutarate and succinate and reduced levels of fumarate and malate. We hypothesize that DC glutamine metabolism after allergen exposure is critical for polarization of Tfh13s. The goals of this proposal are (1) to ascertain effector mechanisms downstream of glutamine metabolism that induce Tfh13 polarization, (2) to elucidate key mechanistic changes in DCs induced by aberrant TCA cycle metabolites, and (3) to determine the translatability of this pathway into human DCs. This work promises an exciting new avenue for development of novel therapeutic targets and preventive strategies for the management of allergic asthma.


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 = $540,579 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Lung Diseases Research	000	3	11/29/2024	NON-COMPETING CONTINUATION	$540,579
														Subtotal = $540,579

Issue Date FY: 2024 ( Subtotal = $594,338 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Lung Diseases Research	000	2	11/13/2023	NON-COMPETING CONTINUATION	$545,820
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Lung Diseases Research	001	2	6/12/2024	NON-COMPETING CONTINUATION	$48,518
														Subtotal = $594,338

Issue Date FY: 2023 ( Subtotal = $553,715 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Lung Diseases Research	000	1	12/25/2022	NEW	$553,715
														Subtotal = $553,715

Grand Total All Awards = $1,688,632

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Metabolic perturbations in conventional dendritic cells modulate Tfh13 induction in asthmatic sensitization

Award Number: R01HL162991

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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