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Prenatal inflammation disrupts blood-brain barrier development and long-term function

Award Number: R01NS126981
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Prenatal inflammation disrupts blood-brain barrier development and long-term function - SUMMARY Maternal immune activation (MIA) during fetal development increases risk for neurodevelopmental disorders (NDDs) later in the offspring life. Chronic microglial activation in the adult offspring exposed to gestational MIA leads to a range of altered behaviors. Yet, the developmental mechanisms whereby MIA induces this sustained activation of offspring brain microglia across the lifespan are not understood. Systemic inflammation triggered during adulthood was shown to disrupt blood-brain barrier (BBB) function, inducing microglial activation, neuroinflammation and leading to the progressive emergence of neuropathologies. Even though comparable outcomes are observed in adult offspring who experienced gestational MIA, whether there is similar BBB disruption and the mechanisms leading to these phenotypes in utero are not known. This is an important knowledge gap because MIA is a risk factor for NNDs and there is growing evidence of vascular dysfunction contributing to the molecular pathology of these disorders. The investigators obtained preliminary data showing that MIA triggered by the viral mimetic poly(I:C) in pregnant mice disrupts fetal BBB formation leading to increased nascent BBB permeability measured using live fetal MRI. Their data further suggest that activation of the cyclooxygenase-2 (COX2; Ptgs2) pathway in fetal brain microglia is causal to MIA effects. Importantly, longitudinal MRI analyses suggest that disruption of fetal BBB formation induces persistent BBB hyperpermeability and life-long brain microglial activation, cerebrovascular inflammation, and behavioral alterations in the offspring. Through the combined expertises of four different research groups, the investigators developed and validated new methods for measuring fetal brain BBB permeability in vivo (MRI) and ex vivo (whole fetus perfusion) which, together with conditional knockout mouse lines, will be used to test: 1) if and how MIA activation of the COX2 pathway in fetal microglia perturbs fetal BBB formation at a critical time of development, leading to incomplete maturation, and 2) if and how the resulting protracted activation of COX2 pathway in resident microglia prolongs BBB structural disruption and neuroinflammation over the offspring lifespan. This self- perpetuating cycle of brain inflammation and BBB disruption would ultimately promote increased risk for neuropathology in the offspring. From an etiological standpoint, this pre-clinical proposal will define novel cellular and molecular pathways involved in life-long effects of prenatal insults, shedding light on the mechanisms by which early inflammation is causally linked to vascular disruptions in neurodevelopmental 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: 2025 ( Subtotal = $436,789 )
2025	2025	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/3/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$436,789
2025	2025	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$240,970
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	6/17/2025	NON-COMPETING CONTINUATION	-$240,970
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $436,789

Issue Date FY: 2024 ( Subtotal = $369,477 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/30/2024	NON-COMPETING CONTINUATION	$26,664
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/24/2023	NON-COMPETING CONTINUATION	$342,813
														Subtotal = $369,477

Issue Date FY: 2023 ( Subtotal = $399,056 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2022	NEW	$399,056
														Subtotal = $399,056

Grand Total All Awards = $1,205,322

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Prenatal inflammation disrupts blood-brain barrier development and long-term function

Award Number: R01NS126981

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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