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MicroRNA regulation of chronic inflammation during aging

Award Number: R01AG079477
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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MicroRNA regulation of chronic inflammation during aging - Abstract Chronic inflammation, referred to as inflammaging , is a risk factor for many age-related chronic conditions (e.g. diabetes, cancer, frailty). Aberrant immune responses may be linked to inflammatory-mediated metabolic and functional disorders but many mechanistic gaps exist. Among recently appreciated regulators of inflammaging are microRNAs (miRNAs). One example of which is the anti-inflammatory miR-146a, where we and others have shown that mice deficient in this miRNA succumb to a life-shortening chronic inflammation that involves clinically relevant comorbidities (1-6). Moreover, deletion of miR-155 in T cells significantly extends the lifespan of miR- 146a·1· mice which points to a vital role for T cell expressed miR-155 in this context including CD4+ T follicular helper (Tfh) cells (3, 5). We have recently expanded our analyses of this critical process by investigating novel pathways in aging T cells that are regulated by miR-155 during inflammaging. By conducting single cell RNA Sequencing (scRNA-Seq) we have identified three gene programs that are counter-regulated by miR-146a and miR-155 in aged T cells that have not been previously examined in this context. These include aerobic glycolysis, chemokine production, and senescence associated secretory phenotype (SASP) factors. Additional preliminary data stemming from initial exploration of these pathways have pointed us to a novel, age-associated inflammatory cos+ T cell subset (Taa cells) that is GZMK CD8 and that expands in both mice and humans (7), and that is regulated by miR-155. Based on these preliminary data, we will carry out the following research aims in an effort to gain substantial new insights into T cell-dependent mechanisms that drive inflammaging and that are regulated by miRNAs. We will also uniquely extend these analyses to young and older adults in efforts to translate our findings to humans. 1) Determine the functional roles of miR-155-induced GZMK+CD8+ T cells during inflammaging. 2) Determine the molecular and metabolic mechanisms underlying miR-155 functions in T cells during inflammaging. 3) Determine if Taa and Tfh cells and their miR-155 levels in older adults correlate with markers of chronic, low-grade inflammation, insulin sensitivity, and muscle strength. We anticipate that this work will unveil key cellular and molecular mechanisms by which miRNAs play pivotal roles in regulating lifespan through their influence on T cell-mediated, age-dependent chronic inflammation. As a result, therapeutically actionable targets will emerge with the potential to limit age-associated human inflammatory diseases that continue to rapidly gain in prevalence in our society.


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 = $564,880 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	000	4	7/14/2025	NON-COMPETING CONTINUATION	$564,880
														Subtotal = $564,880

Issue Date FY: 2024 ( Subtotal = $656,415 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	001	3	6/6/2024	SUPPLEMENT FOR EXPANSION	$80,007
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	000	3	4/18/2024	NON-COMPETING CONTINUATION	$576,408
														Subtotal = $656,415

Issue Date FY: 2023 ( Subtotal = $656,268 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	001	2	5/25/2023	SUPPLEMENT FOR EXPANSION	$80,007
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	000	2	5/8/2023	NON-COMPETING CONTINUATION	$576,261
														Subtotal = $656,268

Issue Date FY: 2022 ( Subtotal = $588,027 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Aging Research	000	1	8/31/2022	NEW	$588,027
														Subtotal = $588,027

Grand Total All Awards = $2,465,590

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MicroRNA regulation of chronic inflammation during aging

Award Number: R01AG079477

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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