Thursday, December 18, 2025 12/18/2025

ROLE OF PERIPHERAL IMMUNE-DERIVED MMP8 IN STRESS SUSCEPTIBILITY

Award Number: R01MH104559
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/24/2014
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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ROLE OF PERIPHERAL IMMUNE-DERIVED MMP8 IN STRESS SUSCEPTIBILITY - ROLE OF PERIPHERAL IMMUNE-DERIVED MMP8 IN STRESS SUSCEPTIBILITY In this application we will examine how peripheral monocytes interface with the brain to mediate stress susceptibility (SUS) vs. resilience (RES). We and others have shown that stress mobilizes monocytes in the periphery by enhancing their proliferation and egress from bone marrow stores into the circulation and the trafficking them to target tissues, such as the brain. While we know that such effects have been linked to alterations in complex stress-related behaviors, the mechanisms by which these immune cells communicate with the brain has been largely unknown. Using single-cell RNA-sequencing along with advanced bioinformatics, we first defined the cellular and molecular pathways that interface monocytes and the brain during chronic social defeat stress (CSDS) exposure in mice. We find that CSDS increases matrix metalloproteinase 8 (MMP8)—a monocyte-enriched matrix metalloproteinase that can remodel the tissue extracellular matrix (ECMs) and promote blood brain barrier (BBB) permeability —in SUS, but not RES, mice. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control ECM reorganization. Depleting MMP8 specifically in peripheral immune cells prevented stress-induced social avoidance behavior and alterations in NAc neurophysiology and extracellular matrix reorganization. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behavior in the context of stress. Our team is now poised to exploit the many state-of-the-art tools in this application to gain a fundamentally more complete understanding of how the peripheral immune system can interface with the brain to control complex stress behaviors. First, we will define exactly how monocyte-derived MMP8 regulates the BBB and ECM reorganization and cell-type specific neurophysiological changes in NAc. We will also define the role of peripheral infiltration of MMP8 in NAc on social and non-social reward/reinforcement behaviors. Together these studies will provide novel insight into the brain-body mechanisms that drive stress susceptibility, with the ultimate goal of developing novel therapeutics targeting MMP8 to treat stress disorders.


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 = $842,950 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	13	12/9/2025	NON-COMPETING CONTINUATION	$842,950
														Subtotal = $842,950

Issue Date FY: 2025 ( Subtotal = $842,950 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	12	12/6/2024	NON-COMPETING CONTINUATION	$716,508
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	002	12	9/18/2025	NON-COMPETING CONTINUATION	$126,442
2025	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	10	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $842,950

Issue Date FY: 2024 ( Subtotal = $842,950 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	11	6/7/2024	COMPETING CONTINUATION	$84,295
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	11	12/13/2023	COMPETING CONTINUATION	$758,655
														Subtotal = $842,950

Issue Date FY: 2023 ( Subtotal = $632,786 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	10	2/2/2023	NON-COMPETING CONTINUATION	$63,278
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	10	11/3/2022	NON-COMPETING CONTINUATION	$569,508
														Subtotal = $632,786

Issue Date FY: 2022 ( Subtotal = $632,786 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	9	5/12/2022	NON-COMPETING CONTINUATION	$63,279
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	9	11/1/2021	NON-COMPETING CONTINUATION	$569,507
														Subtotal = $632,786

Issue Date FY: 2021 ( Subtotal = $632,786 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	8	5/11/2021	NON-COMPETING CONTINUATION	$63,279
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	8	10/30/2020	NON-COMPETING CONTINUATION	$569,507
														Subtotal = $632,786

Issue Date FY: 2020 ( Subtotal = $1,089,839 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	7	11/5/2019	NON-COMPETING CONTINUATION	$599,480
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	002	7	8/18/2020	SUPPLEMENT FOR EXPANSION	$423,750
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	7	2/3/2020	NON-COMPETING CONTINUATION	$66,609
														Subtotal = $1,089,839

Issue Date FY: 2019 ( Subtotal = $666,089 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	003	6	4/3/2019	COMPETING CONTINUATION	$50,926
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	001	6	12/19/2018	COMPETING CONTINUATION	$666,089
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	004	6	9/24/2019	COMPETING CONTINUATION	$0
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	002	5	4/3/2019	NON-COMPETING CONTINUATION	-$50,926
2019	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	5	12/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $666,089

Issue Date FY: 2018 ( Subtotal = $596,882 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	5	5/17/2018	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2017 ( Subtotal = $596,882 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Mental Health Research Grants	000	4	5/20/2017	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2016 ( Subtotal = $596,882 )
2016	2016	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	3	5/18/2016	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2015 ( Subtotal = $596,882 )
2015	2015	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	2	6/20/2015	NON-COMPETING CONTINUATION	$596,882
														Subtotal = $596,882

Issue Date FY: 2014 ( Subtotal = $663,201 )
2014	2014	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL, BOX 3500	NEW YORK-NEW YORK	NY	10029		USA	Mental Health Research Grants	000	1	7/23/2014	NEW	$663,201
														Subtotal = $663,201

Grand Total All Awards = $9,233,865

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ROLE OF PERIPHERAL IMMUNE-DERIVED MMP8 IN STRESS SUSCEPTIBILITY

Award Number: R01MH104559

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/24/2014

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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