Mapping the cellular impacts of CHD8 haploinsufficiency and characterizing microglial activity in CHD8 mutant mice
Active Project Grant Awarded Last action
- Award ID
- F31HD113328
- Recipient
-
University Of California, Davis UEI TX2DAGQPENZ5 Part of State Of California Controllers Office
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $241,496
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date 84% complete
- Place of performance
- Davis, CA, USA
Award details come from USAspending.gov.
Description
- Abstract
- Autism spectrum disorder (ASD) is part of a larger group of neurodevelopmental disorders (ndds) and is diagnosed in more than 1% of the human POPULATION1-3. Patients with severe forms of ASD live with debilitating symptoms that can prevent them from living independent lives. ASD has a strong genetic component, but is genetically HETEROGENOUS1, 4-7. Whole exome studies have identified hundreds of risk loci, including the chromodomain helicase DNA-binding protein 8 (CHD8) GENE2, 8-12. CHD8 is a chromatin remodeling factor (CRF)13-16 and has a high occurrence of DE novo loss-of-function mutations in ASD COHORTS8-11, 17-20. Moreover, along with ASD, CHD8 mutation carriers frequently exhibit intellectual disability (ID), macrocephaly, and GUT DYSFUNCTION21-22. Our lab generated and characterized mice with germline heterozygous loss of function mutations to CHD8, finding macrocephaly and disrupted cognitive function, as well as ASD relevant transcriptional pathology during NEURODEVELOPMENT23. While we and others have characterized CHD8 mutant mouse lines and human in vitro models, the molecular underpinnings of core ASD pathology in CHD8 haploinsufficient mice are still not well understood. CHD8 has been shown to bind regulatory targets in the genome in brain development and adulthood, impacting neurodevelopmental gene expression programs. The primary hypothesis in the field is that CHD8 haploinsufficiency drives ASD pathology by first disturbing neurogenesis and developmental processes, but there may also be disturbances to synaptic function in adulthood that perpetuate and exacerbate cognitive and behavioral SYMPTOMS23-24. In addition to core symptoms, 69% of ASD patients exhibit increased neuroinflammation or microglial ACTIVATION25. Studies on postmortem ASD brain samples indicated increased expression of immune related GENES27-28. The neuroimmune interface in CHD8 haploinsufficient mice has yet to be characterized in significant detail, and the neuroimmune signatures seen in human ASD patients have not previously been observed in mouse models. Intriguingly, our transcriptomic studies have revealed preliminary evidence of perturbed immune pathways in the BRAIN23. Whether these immune symptoms are an intrinsic part of CHD8-mediated pathology or secondary to disruptions in other pathways is uncertain. In this proposal, i will leverage CHD8 mutant mice to elucidate cell-specific transcriptomic mechanisms associated with CHD8 haploinsufficiency and NDD-associated pathology. My studies will secondly test for microglia-specific effects of CHD8 mutation and map the relationship between immune and neuronal signatures in the brain. This work will comprehensively expand the breadth of our understanding of molecular pathology across cell types in the adult brain, as well as interrogate at depth the impacts of CHD8 haploinsufficiency on neuroimmune signaling and microglia. Overall, these studies may provide novel insights into cellular and molecular origins of NDD pathology as well as yield new insights into neuronal-microglial interactions in the brain in severe monogenic ndds.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $576 | |
| Amendment | $33,538 | |
| Amendment | $42,390 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
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| Amendment | $0 | |
| Amendment | $1,280 | |
| Amendment | $40,288 | |
| Amendment | $40,288 | |
| Amendment | $40,288 | |
| Original award | $40,288 |
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Quick answers
Who received award F31HD113328?
F31HD113328 was awarded to University Of California, Davis by National Institute of Child Health and Human Development (National Institutes of Health) on September 1, 2024.
How much is award F31HD113328 worth?
$241,496 has been obligated on F31HD113328.
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