Saturday, July 5, 2025 7/5/2025

High-throughput Functional Analysis of Autism Risk Genes

Award Number: R01MH116002
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2029

Group Awards By:

View Award Description

High-throughput Functional Analysis of Autism Risk Genes - PROJECT SUMMARY There is a critical need to advance from gene discovery to the identification of actionable biological mechanisms in autism spectrum disorders (ASDs). Despite considerable progress in the identification of high confidence genes that are strongly associated with risk, advancing from ASD genes to biologically relevant cellular and circuit mechanisms remains a central challenge. We established a high-throughput zebrafish system for the in vivo functional analysis of multiple ASD genes in parallel. Our analysis of 10 ASD genes in zebrafish mutants revealed novel points of convergence at multiple neurodevelopmental levels and uncovered ASD gene subgroups with shared functional effects. As a critical next step, we will leverage the zebrafish system to analyze the function of 50 ASD genes in parallel at the whole-brain transcriptomic, structural, and circuit levels and translate our findings to human induced pluripotent stem cells (hiPSCs). Our central objectives are to: (1) identify convergent molecular signatures resulting from ASD gene LoF; (2) elucidate novel cellular and circuit mechanisms contributing to whole-brain structural and activity phenotypes; and (3) uncover highly conserved pharmacological pathways downstream of ASD genes. We hypothesize that ASD genes converge on shared molecular, cellular, and circuit mechanisms in the developing vertebrate brain, which will allow us to define novel ASD gene subgroups. This hypothesis is based on compelling evidence for biological convergence across ASD genes from our group and others. To test this hypothesis, we perform molecular phenotyping of ASD gene mutants using whole-brain single nuclear RNA-seq (Aim 1); identify cellular phenotypes contributing to circuit deficits by combining in vivo imaging and cell-type-specific labeling (Aim 2); and conduct parallel pharmacological screens to identify novel phenotypic suppressors in zebrafish and hiPSCs (Aim 3). The expected outcomes of this research are to (1) define convergent molecular, cellular, and circuit phenotypes downstream of ASD genes in the developing vertebrate brain; and (2) leverage the identification of biologically relevant ASD gene subgoups with shared mechanisms to uncover novel pharmacological pathways with translational relevance.


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: 2024 ( Subtotal = $725,869 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	6	9/18/2024	COMPETING CONTINUATION	$725,870
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	5	5/16/2024	NON-COMPETING CONTINUATION	-$1
														Subtotal = $725,869

Issue Date FY: 2022 ( Subtotal = $418,750 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	5	5/13/2022	NON-COMPETING CONTINUATION	$41,875
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	5	12/10/2021	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $418,750

Issue Date FY: 2021 ( Subtotal = $418,750 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	4	6/9/2021	NON-COMPETING CONTINUATION	$41,875
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	4	12/17/2020	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $418,750

Issue Date FY: 2020 ( Subtotal = $657,757 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	002	3	8/14/2020	SUPPLEMENT FOR EXPANSION	$239,007
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	001	3	3/11/2020	NON-COMPETING CONTINUATION	$41,875
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	3	12/19/2019	NON-COMPETING CONTINUATION	$376,875
														Subtotal = $657,757

Issue Date FY: 2019 ( Subtotal = $418,750 )
2019	2019	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	2	12/20/2018	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2018 ( Subtotal = $418,750 )
2018	2018	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Mental Health Research Grants	000	1	2/22/2018	NEW	$418,750
														Subtotal = $418,750

Grand Total All Awards = $3,058,626

Top

All Categories

About

Search

Reports

Data Submission

Award Information

High-throughput Functional Analysis of Autism Risk Genes

Award Number: R01MH116002

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer