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Mutant Shank3 macaque monkeys for neurobiological studies of ASD

突变体 Shank3 猕猴用于自闭症谱系障碍的神经生物学研究

基本信息

批准号：
10553632
负责人：
Robert Desimone
金额：
$ 22.59万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553632
关键词：
Academy Animal Model Animals Behavior Behavioral Biochemical Biological Markers Biomedical Research Brain Brain Diseases CRISPR/Cas technology California China Chinese Clustered Regularly Interspaced Short Palindromic Repeats Cognition Collaborations Communities Complex DNA Sequence Alteration Data Development Electroencephalography Electrons Exhibits Functional Magnetic Resonance Imaging Functional disorder Future Gene Mutation Generations Genes Genome Glutamates Heterozygote Human Impairment Lead Learning Light Macaca Macaca fascicularis Macaca mulatta Mediating Mental disorders Microscopic Modeling Monkeys Mutation Neurobiology Neurosciences Research Pathologic Processes Patients Pattern Phelan-McDermid syndrome Physiology Prefrontal Cortex Primates Research Rest Rodent Scaffolding Protein Science Scientist Short-Term Memory Sleep disturbances Sperm Transport Structure Study models Synapses Synaptic Potentials Technology Testing autism spectrum disorder behavior test cognitive function cohort effective therapy genetic manipulation genome editing motor deficit mouse genome mutant neurobiological mechanism neuroimaging neuropathology neurophysiology nonhuman primate postsynaptic repetitive behavior social social cognition social reciprocity sperm cell therapeutic target therapeutically effective zygote

项目摘要

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.

项目总结/文摘