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Sex-specific trajectories in epigenomic regulation of brain patterning

Award Number: R01MH129301
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Sex-specific trajectories in epigenomic regulation of brain patterning - The core concept of our proposed studies is that sex-biased gene expression early in human development pattern the brain differently in males and females, and that this patterning underlies differential susceptibility of males and females to neurodevelopmental disorders. We envision that these sex differences are regulated by epigenetic programs controlling the expression of developmentally regulated genes in a sex-biased manner. We further postulate that these sex- dependent epigenetic mechanisms interact with genetic risk factors that influence risk, progression, and severity of autism sprectrum disorders (ASD) and schizophrenia (SCZ), and we will test these hypotheses in two specific aims. Aim 1 is to delineate the sex-dependent regulation of early brain development in typical individuals. Epigenetic and gene expression programs in brain organoids and postmortem fetal brains will be evaluated on multiple levels, including transcriptome, proteome, and activity of noncoding regulatory elements. The objective of this aim is to define a network of genes and their regulatory elements—primarily enhancers—that are differentially active between males and females during early brain development. Aim 2 will determine whether the sex-biased regulatory network carries an increased burden of potentially pathogenic or risk associated genetic variants in developmental disorders such as SCZ and ASD. We will query available genome sequencing and GWAS datasets of probands and typical controls to determine whether the sex-biased regulatory network are enriched for rare and common inherited disease variants. Enrichment of these variants in the sex-biased regulatory network will reveal potential mechanisms by which sex-biased gene expression affects SCZ and ASD genetic risk and trajectory. The impact of this work is seeking the first detailed understanding of early sexually dimorphic brain development. The new knowledge will constitute a fundamental advance in our understanding of normal development, and will pioneer the discovery of how disease susceptibility depends on sex-biased gene regulation in the developing 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: 2026 ( Subtotal = $821,296 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	5	2/2/2026	NON-COMPETING CONTINUATION	$821,296
														Subtotal = $821,296

Issue Date FY: 2025 ( Subtotal = $834,436 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	4	9/23/2025	NON-COMPETING CONTINUATION	$125,166
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	4	1/24/2025	NON-COMPETING CONTINUATION	$709,270
														Subtotal = $834,436

Issue Date FY: 2024 ( Subtotal = $943,862 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	3	8/14/2024	NON-COMPETING CONTINUATION	$94,387
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	3	2/13/2024	NON-COMPETING CONTINUATION	$849,475
														Subtotal = $943,862

Issue Date FY: 2023 ( Subtotal = $1,005,819 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	2	3/10/2023	NON-COMPETING CONTINUATION	$1,005,819
														Subtotal = $1,005,819

Issue Date FY: 2022 ( Subtotal = $940,117 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	4/15/2022	NEW	$940,117
														Subtotal = $940,117

Grand Total All Awards = $4,545,530

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Sex-specific trajectories in epigenomic regulation of brain patterning

Award Number: R01MH129301

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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