The impact of DNA methylation on microglial innate immune memory following prenatal immune activation

Active Project Grant Awarded Last action

Award ID
F31MH143445
Recipient
Awarding agency
Obligated
$47,914

Award facts

Assistance listing
93.242 Mental Health Research Grants
Completion date 0% complete
Place of performance
Oklahoma City, OK 73104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

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.

Quick answers

Who received award F31MH143445?

F31MH143445 was awarded to University Of Oklahoma by National Institute of Mental Health (National Institutes of Health) on February 1, 2027.

How much is award F31MH143445 worth?

$47,914 has been obligated on F31MH143445.

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