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Mapping the cellular impacts of Chd8 haploinsufficiency and characterizing microglial activity in Chd8 mutant mice

Award Number: F31HD113328
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Mapping the cellular impacts of Chd8 haploinsufficiency and characterizing microglial activity in Chd8 mutant mice - PROJECT SUMMARY 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.


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: 2026 ( Subtotal = $33,538 )
2026	2026	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	000	3	3/27/2026	NON-COMPETING CONTINUATION	$33,538
														Subtotal = $33,538

Issue Date FY: 2025 ( Subtotal = $42,390 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	002	2	7/15/2025	NON-COMPETING CONTINUATION	$42,390
2025	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	000	1	5/1/2025	TERMINATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	001	1	7/8/2025	OTHER REVISION	$0
														Subtotal = $42,390

Issue Date FY: 2024 ( Subtotal = $41,568 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR, STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	000	1	3/7/2024	NEW	$40,288
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	002	1	4/25/2024	NEW	$0
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Child Health and Human Development Extramural Research	001	1	4/25/2024	NEW	$1,280
														Subtotal = $41,568

Grand Total All Awards = $117,496

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Mapping the cellular impacts of Chd8 haploinsufficiency and characterizing microglial activity in Chd8 mutant mice

Award Number: F31HD113328

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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