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Contribution of maternal immune activation, viral infection and epigenetics to autism--a community-based case control study

Award Number: R01HD109330
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/03/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Contribution of maternal immune activation, viral infection and epigenetics to autism--a community-based case control study - PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a broad range of related neurodevelopmental disorders that are expressed within the first 2 to 3 years of life as stereotypic behaviors, and language and social-emotional impairments. ASD affects about 1 in 59 children in the United States and carries a high economic cost to families and communities. While there is a contribution of heredity, a growing body of research suggests that ASD has origins in utero. Specifically, evidence is accumulating that prenatal inflammation is a critical exposure in the causal pathway of at least a subset of ASD. Notably, this exposure may operate through sex-dimorphic effects on the placenta on fetal brain development, consistent with the high ASD risk for males relative to females. In our community-based hospital population, unique due to mandated universal placental histopathology assessment and linkage to pediatric community care, pilot analyses identified a 3-to-7-fold increased risk of childhood ASD associated with prenatal exposure to acute and/or chronic inflammation (AI, CI). This marker was seen in ~25% of low-risk children eventually diagnosed with ASD. These inflammatory placental pathologies were not marked by any maternal signs or symptoms during pregnancy. In addition, we identified a 13-fold increased odds of ASD risk with placental villous maldevelopment (PVM). We propose here to test pathways from these placental histopathology diagnoses to eventual ASD diagnosis. We will begin with targeted formalin-fixed paraffin-embedded (FFPE) placental histopathology of AI, CI, and PVM. We will then employ detailed and quantitative immunophenotyping of placental-decidual tissue at the placental-maternal interface. We can thoroughly profile cell type, cell function markers, and inflammation activation/apoptosis targets at the same time by using computer-assisted deep learning that allows precise tracking of immunolabeling and minimizes concerns of label overlap that can confound interpretation of immunofluorescent preparations. We will next assess newborn circulating levels of cytokines, chemokines, and growth factors, alterations of which are known to impact neurodevelopmental processes key to the genesis of neuronal dysfunction manifested in ASD. We will also examine epigenetic pathways by assessing DNA methylation in the placenta and its link to inflammation and PVM. Our analyses will test these as pathways from placental/decidual tissue markers of inflammation and/or PVM to ASD diagnosis. No other ASD case-control sample in a community-based population has universal access to FFPE tissue. This proposed project will open a unique window on the prenatal environment underlying ASD. Clarification of the pathways operating in community-based ASD will elucidate the mechanisms involved in ASD risk.


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 = $650,386 )
2025	2025	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1050 FOREST HILL RD	STATEN ISLAND	NY	10314	RICHMOND	USA	Child Health and Human Development Extramural Research	000	3	4/7/2025	NON-COMPETING CONTINUATION	$650,386
														Subtotal = $650,386

Issue Date FY: 2024 ( Subtotal = $596,743 )
2024	2024	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1050 FOREST HILL RD	STATEN ISLAND	NY	10314	RICHMOND	USA	Child Health and Human Development Extramural Research	000	2	6/6/2024	NON-COMPETING CONTINUATION	$596,743
														Subtotal = $596,743

Issue Date FY: 2023 ( Subtotal = $529,893 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1050 FOREST HILL RD	STATEN ISLAND	NY	10314	RICHMOND	USA	Child Health and Human Development Extramural Research	000	1	5/3/2023	NEW	$529,893
														Subtotal = $529,893

Grand Total All Awards = $1,777,022

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Contribution of maternal immune activation, viral infection and epigenetics to autism--a community-based case control study

Award Number: R01HD109330

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/03/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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