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Mutant Shank3 macaque monkeys for neurobiological studies of ASD

Award Number: R01MH121802
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/07/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Mutant Shank3 macaque monkeys for neurobiological studies of ASD - PROJECT SUMMARY/ABSTRACT The ability to genetically modify the mouse genome has revolutionized biomedical research. However, its impact on our understanding of brain disorders is limited partially due to the inherent differences in the structure and physiology of the brain between rodents and humans. Most notably, the prefrontal cortex is one of the largest and most developed portions of the human brain and a top candidate for pathological processes in many psychiatric disorders. Yet, rodents have only a rudimentary prefrontal cortex and are thus limited in exhibiting the complex cognitive functions that are mediated by this region. The lack of predictive animal models is now considered one of the key bottlenecks in developing effective treatments for brain disorders. Non-human primates are much more closely related to humans than are rodents, and this is reflected in their brain development, structure and physiology. Hence, it is increasingly recognized that they provide an attractive model to study higher brain function and brain disorders. The recent development of highly efficient CRISPR genome-editing technology made it feasible to directly manipulate the genome in zygotes, thus expanding genetic manipulations to many species including non-human primates. In the past 4 years, we have been collaborating with a team of scientists in the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology (SIAT), Chinese Academy of Sciences to use CRISPR/Cas9 to generate macaque monkey models of monogenic ASD. We have now successfully generated Shank3 mutant cynomolgus macaques. Shank3 is a glutamatergic postsynaptic scaffolding protein critical for synapse development and function. Heterozygous mutations of the Shank3 gene in humans lead to Phelan-McDermid syndrome (PMS), an autism spectrum disorder. Initial characterization of the 5 founder Shank3 mutant monkeys revealed sleep disturbances, motor deficits, and increased repetitive behaviors, as well as social and learning impairments. Unbiased analysis of fMRI data showed altered local and global connectivity patterns indicative of circuit abnormalities. Together, these results parallel some aspects of the gene-circuit-behavior dysfunction in human ASD and PMS. Here we propose, in collaboration with our colleagues in SIAT, China, to generate F1 generation of Shank3 mutant monkeys to validate initial observations, to further behavioral and neurophysiological characterization and to bring mutant sperms to US for establishing a colony for sharing with autism research community.


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 = $225,900 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	5	1/17/2024	NON-COMPETING CONTINUATION	$203,310
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	5	8/14/2024	NON-COMPETING CONTINUATION	$22,590
														Subtotal = $225,900

Issue Date FY: 2023 ( Subtotal = $225,900 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	4	2/6/2023	NON-COMPETING CONTINUATION	$225,900
														Subtotal = $225,900

Issue Date FY: 2022 ( Subtotal = $225,900 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	001	3	5/23/2022	NON-COMPETING CONTINUATION	$22,590
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	3	1/21/2022	NON-COMPETING CONTINUATION	$203,310
														Subtotal = $225,900

Issue Date FY: 2021 ( Subtotal = $225,900 )
2021	2021	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	2	2/2/2021	NON-COMPETING CONTINUATION	$225,900
														Subtotal = $225,900

Issue Date FY: 2020 ( Subtotal = $225,900 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Mental Health Research Grants	000	1	4/7/2020	NEW	$225,900
														Subtotal = $225,900

Grand Total All Awards = $1,129,500

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Mutant Shank3 macaque monkeys for neurobiological studies of ASD

Award Number: R01MH121802

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/07/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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