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.

项目概要/摘要对小鼠基因组进行基因改造的能力彻底改变了生物医学研究。然而，它对我们对大脑疾病的理解的影响是有限的，部分原因是大脑的固有差异。啮齿动物和人类大脑的结构和生理学。最值得注意的是，前额叶皮层是人脑最大、最发达的部分，也是病理过程的最佳候选者在许多精神疾病中。然而，啮齿类动物只有初级的前额叶皮层，因此在能力方面受到限制。表现出由该区域介导的复杂认知功能。缺乏预测动物模型现在被认为是开发脑部疾病有效治疗方法的关键瓶颈之一。非人类灵长类动物与人类的关系比啮齿类动物更为密切，这反映在他们的大脑发育、结构和生理机能。因此，人们越来越认识到它们提供了一种研究高级大脑功能和大脑疾病的有吸引力的模型。近年来开发的高效 CRISPR基因组编辑技术使得直接操纵受精卵中的基因组成为可能，从而将基因操作扩展到包括非人类灵长类动物在内的许多物种。在过去的 4 年里，我们一直与脑认知和大脑领域的科学家团队合作。中国科学院深圳先进技术研究院脑疾病研究所使用 CRISPR/Cas9 生成单基因 ASD 猕猴模型。我们现在已经成功产生了 Shank3 突变食蟹猴。 Shank3 是一种谷氨酸能突触后支架蛋白对于突触的发育和功能至关重要。人类 Shank3 基因的杂合突变导致费兰-麦克德米德综合征 (PMS)，一种自闭症谱系障碍。 5位创始人的初步特征 Shank3 突变猴子表现出睡眠障碍、运动缺陷和重复行为增加，以及社交和学习障碍。对功能磁共振成像数据的无偏见分析显示局部和全局发生了变化指示电路异常的连接模式。总之，这些结果的某些方面与人类自闭症谱系障碍 (ASD) 和经前综合症 (PMS) 中的基因回路行为功能障碍。在此，我们建议与我们的合作中国SIAT的同事，生成Shank3突变猴的F1代，以验证最初的结果观察，进一步行为和神经生理学特征并将突变精子带到美国建立一个与自闭症研究界共享的群体。