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High-throughput in vivo and in vitro functional and multi-omics screens of neuropsychiatric and neurodevelopmental disorder risk genes

Award Number: RM1MH132648
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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High-throughput in vivo and in vitro functional and multi-omics screens of neuropsychiatric and neurodevelopmental disorder risk genes - PROJECT SUMMARY There is a critical need to develop high-throughput scalable assays to identify biological mechanisms underlying risk genes in neurodevelopmental and neuropsychiatric disorders (NPD). In this proposal, we aim to leverage the unique advantages of two scalable systems – human induced pluripotent stem cells (hiPSCs) and zebrafish – to perform parallel functional assays of NPD genes in vitro and in vivo, and to pilot the development of innovative spatial multi-omics technologies applicable across systems. We propose to establish an Assay and Data Generation Center (ADGC) as part of the SSPsyGene Consortium that capitalizes on the unique and complementary expertise of our labs in large-scale hiPSC CRISPR screens (Brennand), high-throughput zebrafish screens (Hoffman), and cutting-edge multi-omics tool development (Fan). Our goal is to gain novel insights into the convergent and divergent mechanisms by which diverse NPD gene loss of function affects neurodevelopment at the molecular, cellular, structural, circuit, and behavioral levels. We propose to screen 250 NPD genes using a tiered strategy in hiPSCs and zebrafish by conducting pooled and arrayed transcriptomic and phenotypic screens in hiPSCs-derived neurons and glia (Aim 1), CRISPR screens in zebrafish to assess the effects of gene loss of function on whole-brain structure, activity, and basic behaviors (Aim 2), and spatial transcriptomic and multi-omic CRISPR screens to investigate the transcriptional effects of NPD gene disruption in both systems (Aim 3). We will advance the field by identifying biologically relevant phenotypes resulting from NPD gene loss of function across multiple scales, informing gene prioritization schema, and establishing new spatial multi-omics platforms for the functional analysis of NPD genes. These studies will generate an unprecedented resource of matched molecular, cellular, structural, circuit, and behavioral data in hiPSCs and zebrafish, which will be provided for open distribution to the broader community to yield new insights into NPD.


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 = $1,537,668 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	3	5/17/2025	NON-COMPETING CONTINUATION	$1,537,668
														Subtotal = $1,537,668

Issue Date FY: 2024 ( Subtotal = $1,488,732 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	2	4/24/2024	NON-COMPETING CONTINUATION	$1,488,732
2024	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	1/19/2024	NEW	$0
														Subtotal = $1,488,732

Issue Date FY: 2023 ( Subtotal = $1,126,590 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	4/6/2023	NEW	$1,126,590
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	1	4/12/2023	NEW	$0
														Subtotal = $1,126,590

Grand Total All Awards = $4,152,990

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High-throughput in vivo and in vitro functional and multi-omics screens of neuropsychiatric and neurodevelopmental disorder risk genes

Award Number: RM1MH132648

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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