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Role of cytosolic DNA-induced sterile inflammation driving cellular and organismal progeria/aging hallmarks

Award Number: R56AG082759
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Role of cytosolic DNA-induced sterile inflammation driving cellular and organismal progeria/aging hallmarks - Abstract Accumulation of cytosolic DNAs has emerged as a new hallmark of aging that triggers sterile inflammation and contributes to tissue deterioration. However, the mechanisms that generate cytosolic DNAs or the signaling whereby they contribute to aging remain poorly understood. In Hutchinson-Gilford Progeria Syndrome (HGPS), caused by a LMNA gene mutation that encodes a truncated lamin A named “progerin”, we find build-up of cytosolic DNAs, concomitant with profound genomic instability and sterile inflammation. The goal of this proposal is to determine whether this persistent sterile inflammation, which includes an interferon (IFN) response and a senescence-like secretory phenotype, drives metabolic dysfunction and tissue degeneration in progeria, and to define the mechanisms involved. Deciphering the mechanisms controlling sterile inflammation in aging/progeria will provide novel strategies to improve healthy aging and reduce the severity of diseases like HGPS. Our in vitro and in vivo data show that STING and STAT1 drive progeroid phenotypes. Indeed, pharmacological, or genetic inhibition of STING and STAT1 repressed sterile inflammation and improved cellular hallmarks of aging and, critically, targeting STAT1 increased the healthspan and the lifespan of progeria mice. Yet, the molecular mechanisms whereby progerin engages STING and STAT1 activities, and the roles played by STING and STAT1 triggering metabolic alterations and tissue degeneration in progeria are unknown. Unexpectedly, our data also show that progerin does not trigger the canonical cGAMP-dependent mode of STING-STAT1 pathway activation. This proposal aims to define the non-canonical mode of STING stimulation upon progerin-induced accumulation of cytosolic DNAs (Aim 1), the role that STING, STAT1, and downstream interferon stimulated genes such as ISG15 play driving cellular metabolic alterations (Aim 2), and the contribution of STING-STAT1- ISG15 pathway to tissue degeneration/loss and reduced healthspan and lifespan of progeria mice (Aim 3). If successful, our studies will demonstrate that a fundamental mechanism driving progeria is the maladaptive response to nuclear/mitochondrial damage and accumulation of cytosolic DNAs, which lead to a sustained and unresolved sterile inflammation/IFN response that compromises metabolism and tissue homeostasis. Demonstrating that cytosolic DNA-triggered pathways drive metabolic dysfunction and tissue loss in progeria, defining the mechanisms involved, and showing that targeting specific factors in the pathway in vivo has beneficial effects, will have important and potentially transformative therapeutic implications for this devastating and uncurable disease, which will likely be relevant to metabolic phenotypes during normal aging.


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	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Aging Research	000	1	1/28/2026	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $378,750 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Aging Research	000	1	9/19/2023	NEW	$378,750
														Subtotal = $378,750

Grand Total All Awards = $378,750

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Role of cytosolic DNA-induced sterile inflammation driving cellular and organismal progeria/aging hallmarks

Award Number: R56AG082759

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/20/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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