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Targeted inhibition of stress associated pathways to promote resilience against maternal immune activation

Award Number: R15MH114035
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Targeted inhibition of stress associated pathways to promote resilience against maternal immune activation - Clinical evidence suggests that exposure to maternal immune activation (MIA) during the prenatal period (e.g., having the flu during pregnancy) increases the susceptibility for neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. These disorders are associated with the manifestation of a heterogeneous set of symptoms, including social impairments, which emerge in later life. The mechanistic underpinnings of these social disruptions and how they interact with the environment are not well understood but are a likely path for identifying factors contributing to resilience vs susceptibility against challenges to mental health functioning. Using an animal model, we aim to determine how this adverse early health experience alters the development of brain circuitry in males and females, to find preventative interventions and treatments. Our recent work shows that MIA causes an overexpression of the stress sensitive gene corticotropin releasing factor (Crh), and its associated receptor Crhr1, in areas of the brain central to social behavior and cognition. Housing pregnant dams in environmental enrichment (a translationally relevant intervention) protects the fetus by maintaining the placental 11-beta hydroxysteroid dehydrogenase (11HSD)1 and 11HSD2 metabolism of maternal corticosterone at the time of prenatal immune challenge; this housing condition also protects against Crh and Crhr1 overexpression and related social impairments associated with MIA. To confirm that excessive levels of maternal plasma corticosterone are responsible for the later life overexpression of stress sensitive genes and social impairments (Aim 1), we will employ a clinically available inhibitor of cytochrome P450 11B1, mitochondrial (11β-hydroxylase), the enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex. We will use this inhibitor to attenuate the endocrine activation associated with MIA to test if this prevents these MIA-induced neural and social changes. Relatedly, we will explore protection against MIA-associated changes in Crhr1 signaling mechanisms and epigenetic machinery. In Aim 2, we will use a Crhr1 antagonist to determine if this pharmacological intervention can prevent and/or reverse the effects of MIA on social behaviors. Finally, using viral tools, we will begin studies to evaluate whether targeted deletion of Crhr1 can prevent the social consequences of MIA, and if overexpression can in turn counteract the protective effects of environmental enrichment housing. Together, these studies will help identify and confirm mechanisms by which clinically utilized environmental manipulations, such as enrichment, offer protection to the developing brain.


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 = $0 )
2025	2022	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	3/5/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $383,006 )
2022	2022	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	003	2	8/11/2022	COMPETING CONTINUATION	$1,476
2022	2022	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	2	2/17/2022	COMPETING CONTINUATION	$383,006
2022	2020	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	1	8/11/2022	SUPPLEMENT FOR EXPANSION	-$1,476
2022	2018	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	2/16/2022	NEW	$0
														Subtotal = $383,006

Issue Date FY: 2020 ( Subtotal = $27,500 )
2020	2020	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	1	4/13/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	4/7/2020	SUPPLEMENT FOR EXPANSION	$27,500
														Subtotal = $27,500

Issue Date FY: 2018 ( Subtotal = $377,550 )
2018	2018	MCPHS UNIVERSITY	179 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	5/31/2018	NEW	$377,550
														Subtotal = $377,550

Grand Total All Awards = $788,056

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Targeted inhibition of stress associated pathways to promote resilience against maternal immune activation

Award Number: R15MH114035

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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