Characterization of SynGAP Mutations in Human Cognitive Disorders

人类认知障碍中 SynGAP 突变的表征

基本信息

批准号：
10094253
负责人：
Richard L Huganir
金额：
$ 52.89万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10094253
关键词：
Affect Animal Behavior Behavior Behavioral Behavioral Assay Biochemical Bipolar Disorder C2 Domain CRISPR/Cas technology Cognition Cognition Disorders Copy Number Polymorphism Data Dendritic Spines Development Disease Drug Screening Electrophysiology (science)Electroporation Etiology FMR1 FMRP Frameshift Mutation Functional disorder GTPase-Activating Proteins Generations Genes Genetic study Genome Glutamates Human Impairment In Vitro Intellectual functioning disability Investigation Knock-in Mouse Lead Ligands Mediating Mental disorders MicroRNAs Molecular Morphogenesis Mus Mutation Neuraxis Neurodevelopmental Disorder Neurons Onset of illness PH Domain Patients Phenotype Phosphorylation Site Protein Biosynthesis Proteins Risk Risk Factors Role SH3 Domains Schizophrenia Signal Pathway Signal Transduction Signal Transduction Pathway Structure Synapses Synaptic Transmission Synaptic plasticity Techniques Testing Therapeutic Translations Variant Vertebral column autism spectrum disorder base behavioral phenotyping calmodulin-dependent protein kinase II comorbidity density disorder risk genome editing genome wide association study high throughput screening human disease improved in utero in vivo in vivo Model insight mouse model mutant mouse model neural circuit neuronal circuitry neuropsychiatric disorder novel therapeutic intervention postsynaptic real-time images response risk variant small molecule tool transmission process

项目摘要

Project Summary Recent genome-wide association studies of Intellectual disability (ID), Autism spectrum disorder (ASD) and Schizophrenia (SCZ) have improved our understanding of the molecular and cellular basis of human cognitive diseases. Functional categorization of these genes has revealed a significant enrichment of mutations affecting glutamatergic synapse structure and function. One protein that has been shown to regulate glutamatergic synapses is SynGAP, a RasGAP that is a critical negative regulator of spine morphogenesis and synaptic plasticity via Ras-ERK and protein synthesis-dependent signaling pathways. De Novo deleterious SYNGAP mutations are estimated to account for approximately 1% of ID cases and are highly comorbid with ASD. SYNGAP variants have also been found to be a significant risk factor in other neuropsychiatric disorders including SCZ and bipolar disorder (BP). We recently identified SynGAP as one of the most potent regulators of synaptic size and/or number using a high-throughput screen of 200 SCZ-associated risk genes. In addition, we found that ID/ASD-associated SynGAP mutations also affect synaptic structure and function. These data support the notion that human SynGAP mutations might alter synaptic transmission and plasticity. To determine how disease-associated SynGAP mutations impact synaptic pathophysiology and behavior, we will first characterize the effect of SYNGAP disease risk variants on synapse structure and function using a combination of approaches including real time imaging, biochemical and electrophysiological techniques. Next, we will use CRISPR/Cas9 genome editing to generate mouse models carrying SynGAP mutations that precisely mimic human disease risk variants of SynGAP. With these mice we will determine whether they have differential plasticity, circuit and behavioral phenotypes. Finally, we will perform mechanism based drug screens to target disrupted SynGAP-regulated signal transduction pathways to discover small molecule(s) that can ameliorate synaptic and behavioral deficits. This proposed project would be the first systematic investigation of disease-associated SynGAP mutations on synaptic pathophysiology and animal behavior. These studies will allow us to gain insight into mechanisms underlying SynGAP-associated diseases and pave the way for novel therapeutic strategies.

项目概要最近关于智力障碍（ID）、自闭症谱系障碍（ASD）和精神分裂症（SCZ）提高了我们对人类认知的分子和细胞基础的理解疾病。这些基因的功能分类揭示了影响的突变显着丰富谷氨酸能突触的结构和功能。一种已被证明可以调节谷氨酸能的蛋白质突触是 SynGAP，一种 RasGAP，是脊柱形态发生和突触的关键负调节因子通过 Ras-ERK 和蛋白质合成依赖性信号通路实现可塑性。 De Novo 有害 SYNGAP 据估计，突变约占 ID 病例的 1%，并且与 ASD 高度共存。 SYNGAP 变异也被发现是其他神经精神疾病的重要危险因素包括 SCZ 和双相情感障碍 (BP)。我们最近发现 SynGAP 是最有效的调节剂之一使用 200 个 SCZ 相关风险基因的高通量筛选来确定突触大小和/或数量。此外，我们发现 ID/ASD 相关的 SynGAP 突变也会影响突触结构和功能。这些数据支持人类 SynGAP 突变可能改变突触传递和可塑性的观点。到确定疾病相关的 SynGAP 突变如何影响突触病理生理学和行为，我们将首先使用以下方法描述 SYNGAP 疾病风险变异对突触结构和功能的影响结合实时成像、生化和电生理学技术等方法。下一个，我们将使用 CRISPR/Cas9 基因组编辑来生成携带 SynGAP 突变的小鼠模型精确模仿 SynGAP 的人类疾病风险变体。通过这些小鼠，我们将确定它们是否具有差异可塑性、电路和行为表型。最后，我们将进行基于机制的药物筛选以受干扰的 SynGAP 调节的信号转导途径为目标，以发现能够可以改善突触和行为缺陷。该拟议项目将是第一个系统性的研究疾病相关的 SynGAP 突变对突触病理生理学和动物行为的影响。这些研究将使我们能够深入了解 SynGAP 相关疾病的潜在机制，并为新的治疗策略的途径。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Context-dependent hyperactivity in syngap1a and syngap1b zebrafish autism models.

syngap1a 和 syngap1b 斑马鱼自闭症模型中的情境依赖性过度活跃。

DOI：
10.1101/2023.09.20.557316
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Sumathipala,SureniH;Khan,Suha;Kozol,RobertA;Araki,Yoichi;Syed,Sheyum;Huganir,RichardL;Dallman,JuliaE
通讯作者：
Dallman,JuliaE

Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection.

DOI：
10.7554/elife.75707
发表时间：
2022-04-08
期刊：
ELIFE
影响因子：
7.7
作者：
Kilinc, Murat;Arora, Vineet;Creson, Thomas K.;Rojas, Camilo;Le, Aliza A.;Lauterborn, Julie;Wilkinson, Brent;Hartel, Nicolas;Graham, Nicholas;Reich, Adrian;Gou, Gemma;Araki, Yoichi;Bayes, Alex;Coba, Marcelo;Lynch, Gary;Miller, Courtney A.;Rumbaugh, Gavin
通讯作者：
Rumbaugh, Gavin