Contribution of maternal immune activation, viral infection and epigenetics to autism – a community-based case control study
Active Project Grant Awarded Last action
- Award ID
- R01HD109330
- Recipient
-
Research Foundation For Mental Hygiene Inc. UEI LKEPMM3KKF27 Part of Research Foundation For Mental Hygiene Inc.
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,997,294
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date 71% complete
- Place of performance
- Staten Island, NY 10314, USA
Award details come from USAspending.gov.
Description
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $623,529 | |
| Amendment | $650,386 | |
| Amendment | $596,743 | |
| Amendment | $596,743 | |
| Original award | $529,893 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Wayne State University | $79,745 | |
| Wayne State University | $101,859 | |
| Subrecipient not on record | $34,652 | |
| University Of California, Davis | $80,314 | |
| Michigan State University | $135,416 | |
| Wayne State University | $11,315 | |
| Wayne State University | $10,851 |
Quick answers
Who received award R01HD109330?
R01HD109330 was awarded to Research Foundation For Mental Hygiene Inc. by National Institute of Child Health and Human Development (National Institutes of Health) on May 3, 2023.
How much is award R01HD109330 worth?
$2,997,294 has been obligated on R01HD109330.
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