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High-throughput modeling of autism risk genes using zebrafish

Award Number: R01MH121601
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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High-throughput modeling of autism risk genes using zebrafish - Autism spectrum disorder (ASD) is caused by both environmental and genetic factors, with the genetic contribution estimated at 60-80%. Dozens of genes that increase risk for ASD have been identified, most based on de novo mutations, but these mutations are predicted to account for only 15-20% of ASD cases. Thus, the majority of the genetic contribution to ASD is predicted to result from common and rare inherited variation, but few such genes have been identified. Recently, using whole genome sequencing, we reported genome wide evidence for >60 ASD risk genes, 26 of them novel for ASD, with signals derived from inherited and de novo protein truncating or missense mutations. The functions of most of these genes are unknown, so a crucial and necessary next step is to explore their impact on neurodevelopment and neuronal function using a model organism. The current pace of translating genetic risk factors into phenotypes, mechanisms and therapies is limited in part by inefficiencies with in vivo mammalian model systems, which makes them impractical for creating and behaviorally testing large numbers of mutant lines. Here, we leverage the zebrafish, which occupies a unique niche as a vertebrate model with features amenable to both in vivo screening and mechanistic understanding, including ex utero development, transparency, small size, rapid development, a conserved yet relatively simple vertebrate brain, behaviors relevant to ASD, and cost-effectiveness relative to mammalian models. While the zebrafish cannot recapitulate ASD and has limitations for modeling a human disorder, an emerging literature supports the notion that it is a useful model to study the functions of genes that contribute to ASD risk. Rather than assess ASD-risk genes one at a time, we will accelerate progress towards mechanistic understanding via high-throughput assays and analyses. In Specific Aim 1 we will generate null mutations in the zebrafish orthologs of 24 high confidence, novel, genome-wide significant ASD risk genes, and systematically test each mutant for neurodevelopmental, behavioral, neuronal network, and transcriptomic phenotypes. In Specific Aim 2, we will use transcriptomic analyses, at the whole brain and single cell levels, to integrate ASD risk genes into functional networks, and test for convergence across genes and species, including ASD post mortem brain. We will also test for functional associations among behavioral phenotypes that are often co-morbid in ASD, such as disrupted sleep and social behavioral deficits. In Specific Aim 3 we will perform mechanistic studies to understand how mutation of specific ASD-risk genes leads to phenotypes. This project will efficiently and cost-effectively create and characterize vertebrate animal models for a large number of novel ASD risk genes. These animal models will be a valuable resource for the community, particularly for large-scale in vivo drug screens to identify new therapies for ASD.


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 = $0 )
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	5	11/20/2025	NON-COMPETING CONTINUATION	$0
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	5	11/21/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	5	4/23/2025	NON-COMPETING CONTINUATION	$0
2025	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	5	4/24/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $850,887 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	5	8/26/2024	SUPPLEMENT FOR EXPANSION	$94,784
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	5	8/23/2024	NON-COMPETING CONTINUATION	$756,103
														Subtotal = $850,887

Issue Date FY: 2023 ( Subtotal = $850,103 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	002	4	9/7/2023	SUPPLEMENT FOR EXPANSION	$11,484
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	001	4	8/28/2023	SUPPLEMENT FOR EXPANSION	$82,516
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	4	8/18/2023	NON-COMPETING CONTINUATION	$756,103
														Subtotal = $850,103

Issue Date FY: 2022 ( Subtotal = $756,552 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	3	8/31/2022	NON-COMPETING CONTINUATION	$756,552
														Subtotal = $756,552

Issue Date FY: 2021 ( Subtotal = $756,837 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	2	8/31/2021	NON-COMPETING CONTINUATION	$756,837
														Subtotal = $756,837

Issue Date FY: 2020 ( Subtotal = $811,759 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Mental Health Research Grants	000	1	9/15/2020	NEW	$811,759
														Subtotal = $811,759

Grand Total All Awards = $4,026,138

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High-throughput modeling of autism risk genes using zebrafish

Award Number: R01MH121601

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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