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Gene regulatory networks influencing neuron-microglia interactions in fetal brain development.

Award Number: R00MH129983
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Gene regulatory networks influencing neuron-microglia interactions in fetal brain development. - Project Summary/Abstract The prenatal period is a sensitive and critical time for brain development characterized by waves of neurogenesis, neuronal migration, and formation of neural networks. In the first and second trimester, microglia are the dominant immune cells of the brain and participate in a variety of processes essential to brain development, including secreting neurotropic factors and engulfing apoptotic neural progenitor cells. Fetal microglia dysfunction can lead to aberrant cortical lamination, resulting in an increased risk of brain pathology. We have identified numerous ligand-receptor pairs involved in microglia-to-cortex and cortex-to-microglia signaling predicted to contribute to human fetal microglia function and fetal brain development. We observe concordant expression of these ligand-receptors pairs in cerebral organoids (COs) and induced pluripotent stem cell-derived microglia with our human fetal data. COs can model early human brain development, but current models lack the immune component of the brain. Our data suggest that induced pluripotent stem cell-derived microglia co- cultured with COs (oMGs) capture significant phenotypic characteristics of human fetal microglia. Thus, a systematic analysis of neural maturation following integration of microglia into COs is the first step in using this model system to interrogate the molecular mechanisms underlying how neuron-microglia interactions establish early brain circuitry. This proposal aims to use COs and oMGs to assess how brain environment signals and corresponding transcription factors contribute to fetal microglia behavior and microglial interaction with neurons in early fetal development. In Aim 1, completed in the K99 phase, I will test the hypothesis that integration of microglia into COs results in enhanced neural maturation. Additionally, I will test how perturbation of homeostatic brain environment signaling in microglia results in microglia dysfunction and altered neuronal subpopulations. In Aim 2, I will identify transcription factor networks underlying human and mouse microglia behavior throughout development, at homeostasis and after an inflammatory insult. The goal for Aim 2 is to uncover species- conserved mechanisms in microglia responses to inflammation for improved therapeutic targeting and murine modeling and to discover potential human-specific risk factors for disease. Additionally, I will test the hypothesis that microglial developmental transcriptional factors are re-wired following an inflammatory insult, leading to long- lasting changes in microglia behavior and disruption of brain circuitry. Studies in Aim 2 will be completed in the independent phase. My long-term goal is to elucidate the epigenetic mechanisms underlying neuronal-microglia communication in health and disease as an independent investigator. I have assembled a diverse group of highly skilled mentors who will ensure that I receive extensive training in neurodevelopment and assessment of neural circuits. My training will be further enhanced by the unique scientific environment of the UCSD research community, which is geared towards the development and usage of cutting-edge technology and analytic methods to assess cellular heterogeneity and dynamic cell-cell interactions in the brain.


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: 2025 ( Subtotal = $204,282 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	4	4/30/2025	NON-COMPETING CONTINUATION	$0
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	002	4	5/23/2025	NON-COMPETING CONTINUATION	$0
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	000	4	3/7/2025	NON-COMPETING CONTINUATION	$204,282
														Subtotal = $204,282

Issue Date FY: 2024 ( Subtotal = $286,483 )
2024	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Mental Health Research Grants	001	3	7/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$62,383
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Mental Health Research Grants	000	3	6/19/2024	EXTENSION WITH OR WITHOUT FUNDS	$224,100
														Subtotal = $286,483

Grand Total All Awards = $490,765

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Gene regulatory networks influencing neuron-microglia interactions in fetal brain development.

Award Number: R00MH129983

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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