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The Impact of DNA Methylation on Microglial Innate Immune Memory Following Prenatal Immune Activation

Award Number: F31MH143445
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2027
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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The Impact of DNA Methylation on Microglial Innate Immune Memory Following Prenatal Immune Activation - ABSTRACT Neurodevelopmental disorders are a major contributor to the mental health burden of children in the United States. Epidemiologic studies revealed prenatal exposure to early-life stressors increases the risk for neurodevelopmental disorders with maternal inflammation as a common underlying factor. During gestation, microglia, the innate immune cells in the brain, play a crucial role in neurodevelopment by responding to maternal inflammation, pruning synapses, and mediating cell-to-cell interactions. Due to their high plasticity and long-life, microglia can develop an innate immune memory (IIM) in which microglial responses to secondary stressors are either increased or diminished. Specifically, microglia exposed to robust or repeated environmental cues induce a priming (more activated) or tolerizing (less activated) response. To model the human epidemiologic data, we use a mouse model of maternal inflammation called maternal immune activation (MIA) which induces neural and behavioral deficits relevant to neurodevelopmental disorders. Interestingly, microglia from the offspring of MIA treated dams showed a blunted immune response to a secondary immune challenge during adulthood indicative of innate immune tolerance. However, the mechanism by which prenatal inflammatory stimuli induce IIM in microglia remains unexplored. One clue to the mechanism of microglia IIM came from the observation that microglia from MIA offspring showed a more open chromatin structure but reduced transcription factor (TF) recruitment of immune response TFs. Therefore, we hypothesize that prenatal inflammation epigenetically induces IIM in microglia through DNA methylation leading to tolerance of the microglia and subsequent dampening of the immune reactivity. To test this hypothesis, I will perform the following aims. First, I will assess global DNA methylation in microglia across development in MIA and control mice using a mixture of DNA methylation antibodies and DNA modification sequencing. Second, I will determine the functional requirement of DNA methylation during prenatal immune stress on microglia immune reactivity by inducing DNA hypomethylation using both a pharmacologic approach and a microglia-specific DNA methyltransferase 3b (Dnmt 3b) knockout mouse model in tandem with MIA. I will assess the functional role of DNA methylation in IIM imprinting using bulk RNA-sequencing, in vitro cytokine release assays, and histological approaches to examine microglial activation. Our study will provide insight into the role of DNA methylation in microglia reactivity and how it may imprint IIM of a developmental stressor. Furthermore, I will gain essential training in technical (DNA modification sequencing, quantitative microcopy), intellectual (biostatistics, science communication), and professional (mentoring, teaching, collaboration) skills equipping to achieve my goal of becoming an independent researcher. My mentorship team has broad expertise across the training areas and a strong record of mentorship ensuring a well-rounded training environment that supports my scientific aims and long-term success in academia.


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 = $47,914 )
2026	2026	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 560	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Mental Health Research Grants	000	1	8/6/2026	NEW	$47,914
														Subtotal = $47,914

Grand Total All Awards = $47,914

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The Impact of DNA Methylation on Microglial Innate Immune Memory Following Prenatal Immune Activation

Award Number: F31MH143445

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2027

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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