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miR-342, a novel glucocorticoid-responsive miRNA necessary for Foxp3+ regulatory T cell function

Award Number: R21AI172135
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: 01/18/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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miR-342, a novel glucocorticoid-responsive miRNA necessary for Foxp3+ regulatory T cell function - Abstract Foxp3+ regulatory T cells (Treg) are the central regulators of immunity and tolerance. Defects in Treg generation and/or functions lead to lethal systemic autoimmune inflammation in both mice and human, demanding a tight regulation of Treg homeostasis. Determining factors capable of modulating Treg function is thus a subject of utmost importance. Among the factors is microRNA, a small non-coding RNA molecule known to regulate gene expression. There is plethora of evidence that miRNAs play a critical role in Treg generation and functions. However, our understanding the mechanisms by which Treg-derived miRNA modulates Treg functions is relatively limited. Glucocorticoids are the frontline treatment option for many inflammatory diseases, including autoimmunity and allergy. Despite the broad use, the precise immune suppressive mechanisms used by glucocorticoids remain largely elusive. We recently reported that Tregs are indispensable during glucocorticoid- induced treatment of chronic inflammation. Mechanistically, we uncovered that a novel miR-342 is induced by glucocorticoid stimulation in Tregs and that miR-342 targets metabolic regulator, Rictor, to control Treg metabolic programming. From the preliminary studies we also found that miR-342 is highly expressed in Tregs and that it is further enhanced by dexamethasone (Dex) stimulation. Interestingly, miR-342 expression in Tregs appears to be critical for Treg suppressive function. Moreover, miR-342 was also detected in the serum following Dex treatment. To our surprise, Dex-induced serum miR-342 was detected in steroid-sensitive but not in steroid- resistant inflammation. Based on the compelling evidence, we propose the hypothesis that miR-342 is a glucocorticoid-induced miRNA in Tregs that plays a regulatory role in Tregs’ ability to control inflammation. Two specific aims are proposed. First, we will determine the role of miR-342 in Treg functions. Two newly generated animal models in which Tregs lack or overexpress miR-342 will be used. Second, we will examine the role of Treg-derived miR-342 in steroid resistance. Identification of the mechanisms by which glucocorticoid-induced miR-342 regulates Treg functions will open novel opportunities to develop therapies applicable to manage severe inflammatory conditions including steroid resistance.


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: 2026 ( Subtotal = $0 )
2026	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	2	5/7/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $240,000 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	2	12/13/2023	NON-COMPETING CONTINUATION	$216,000
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	001	2	5/17/2024	NON-COMPETING CONTINUATION	$24,000
														Subtotal = $240,000

Issue Date FY: 2023 ( Subtotal = $200,000 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/18/2023	NEW	$200,000
														Subtotal = $200,000

Grand Total All Awards = $440,000

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miR-342, a novel glucocorticoid-responsive miRNA necessary for Foxp3+ regulatory T cell function

Award Number: R21AI172135

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: 01/18/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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