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The Contribution of Microglial MEF2C to Brain Development

Award Number: R01NS124637
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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The Contribution of Microglial MEF2C to Brain Development - Summary/Abstract Intellectual disability and autism spectrum disorders are devastating disorders thought to arise from a combination of synaptic dysfunction and altered neural progenitor modulation for which there are no effective treatments. Mutations or deletions in one allele of myocyte enhancer factor 2C (MEF2C) result in MEF2C Haploinsufficiency Syndrome (MHS), a disorder characterized by a severe phenotype with intellectual disability, repetitive motor behaviors, and difficulties with communication and social interaction on the autism spectrum. We have found that MEF2C is highly expressed in human microglia during neurodevelopment and have identified MEF2C as a core transcription factor involved in the microglial cell fate. Furthermore, MEF2C expression is regulated by the brain environment and decreases during aging. Microglia have not been extensively investigated in the pathogenesis of neurodevelopmental disorders, but there is increasing evidence for their impact on brain development suggesting they may contribute to especially the social and behavioral deficits in autism. The central hypothesis is that microglial MEF2C has a crucial role in human brain development and contributes to neurodevelopmental disorders including intellectual disability and autism pathogenesis and the resulting behavioral phenotype. We will utilize novel in vitro and in vivo methods to ascertain the role of microglial MEF2C in brain development including synapse retention and pruning, modulation of the neural progenitor pool, and microglial development. The project goal is to test the hypothesis that MEF2C specifically in human microglia contributes to brain development and reduced expression contributes to neurodevelopmental deficits found in intellectual disability and autism. Delineating MEF2C transcriptional and environmental targets using epigenetic techniques will yield novel insight into human microglial transcriptional networks and expand on our knowledge of autism associated genes with the potential to yield novel therapeutic targets. The long-term goal is to generate and validate methods using human microglia specifically which can be utilized for drug screening and to generate preclinical data in order to ultimately identify novel potential therapeutic targets to improve the outcomes for children with autism.


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: 2027 ( Subtotal = $0 )
2027	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2026 ( Subtotal = $408,929 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/23/2025	NON-COMPETING CONTINUATION	$368,037
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	3/24/2026	NON-COMPETING CONTINUATION	$40,892
														Subtotal = $408,929

Issue Date FY: 2025 ( Subtotal = $408,929 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/19/2024	NON-COMPETING CONTINUATION	$368,037
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/8/2025	NON-COMPETING CONTINUATION	$40,892
														Subtotal = $408,929

Issue Date FY: 2024 ( Subtotal = $396,661 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/20/2023	NON-COMPETING CONTINUATION	$368,037
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/23/2024	NON-COMPETING CONTINUATION	$28,624
														Subtotal = $396,661

Issue Date FY: 2023 ( Subtotal = $408,929 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/19/2022	NON-COMPETING CONTINUATION	$368,037
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/30/2023	NON-COMPETING CONTINUATION	$40,892
														Subtotal = $408,929

Issue Date FY: 2022 ( Subtotal = $408,929 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/27/2021	NEW	$408,929
														Subtotal = $408,929

Grand Total All Awards = $2,032,377

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The Contribution of Microglial MEF2C to Brain Development

Award Number: R01NS124637

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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