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Transcriptional and metabolic regulation of Treg cell specification for the control of allergic airway disease

Award Number: R01AI153255
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 Acquisition of the TH2 suppressor program specializes Treg cell function in preventing the development of allergic airway inflammation associated with asthma. Airway allergic responses arise when there is ineffective development of tolerance to normally harmless environmental antigens and activation of pro-allergic TH2 responses. Cooperation of Foxp3 with additional transcription factors is crucial for establishing this specific function. Aside from the transcriptional regulation, reprogramming of cellular metabolism represents an important regulatory mechanism underlying Treg cell homeostasis and function. However, it remains elusive how Treg cells coordinate immune signaling and cellular metabolism with Treg cell functional specification in the control of allergic airway disease (AAD). We recently demonstrated that liver kinase B1 (LKB1), an important regulator of cellular metabolism, is indispensable for Treg cells in suppressing allergic airway inflammation. In our preliminary studies, we found that loss of LKB1 resulted in impaired expression of BATF and function of IRF4 in Treg cells. By generating a new mouse model with Treg-specific ablation of BATF, we revealed that BATF-deficient Treg cells selectively lost their capabilities of restraining TH2-mediated lung inflammation. Moreover, we observed that lung-resident Treg cells displayed higher levels of cellular triacylglycerols (TAGs) than splenic Treg cells from mice with lung inflammation. Loss of LKB1 and BATF in Treg cells enhanced biosynthesis of unsaturated fatty acids (UFAs) and TAGs, both associated with increased expression of SCD1 and DGAT2, the rate-limiting enzymes for synthesis of UFAs and TAGs, respectively. Finally, suppressing SCD1 and DGAT2 reduced levels of cellular lipids and concomitantly increased Foxp3 expression. We hypothesize that LKB1 signaling links activation of a BATF/IRF4-dependent transcriptome and regulation of UFA and TAG biosynthesis with Treg cell functional specification for the control of allergic airway disease. Specifically, we will test this hypothesis in two specific Aims: (1) Determine how the LKB1-BATF/IRF4 axis orchestrates the TH2 suppressor program in Treg cells for the control of allergic airway disease; (2) Determine if regulation of UFA and TAG biosynthesis alters Treg cell function in preventing AAD. Studies from this application may advance our understanding of how Treg cells coordinate transcriptional activation and regulation of lipid biosynthesis in orchestrating the TH2 suppressor program and manifest therapeutic opportunities for treating AAD.


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 = $499,162 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	4	4/11/2024	NON-COMPETING CONTINUATION	$499,162
														Subtotal = $499,162

Issue Date FY: 2023 ( Subtotal = $505,502 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	3	4/19/2023	NON-COMPETING CONTINUATION	$505,502
														Subtotal = $505,502

Issue Date FY: 2022 ( Subtotal = $502,332 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	2	4/15/2022	NON-COMPETING CONTINUATION	$502,332
														Subtotal = $502,332

Issue Date FY: 2021 ( Subtotal = $447,387 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	1	5/18/2021	NEW	$447,387
														Subtotal = $447,387

Grand Total All Awards = $1,954,383

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Transcriptional and metabolic regulation of Treg cell specification for the control of allergic airway disease

Award Number: R01AI153255

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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