Characterization of SynGAP Mutations in Human Cognitive Disorders

人类认知障碍中 SynGAP 突变的表征

• 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
• 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; 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

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.

项目摘要 全基因组智力残疾（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突变的显着富集 谷氨酸能突触结构和功能。一种已显示用于调节谷氨酸能的蛋白质 突触是Syngap，这是一种rasgap，是脊柱形态发生和突触的关键负调节剂 通过RAS-ERK和蛋白质合成依赖性信号通路的可塑性。从头有害的syngap 估计突变约占ID病例的1％，并且与ASD高度合并。 还发现Syngap变体是其他神经精神疾病的重要危险因素 包括SCZ和躁郁症（BP）。我们最近将Syngap确定为最有效的调节器之一 使用200个与SCZ相关的风险基因的高通量屏幕的突触大小和/或数字。此外， 我们发现ID/与ASD相关的合成突变也影响突触结构和功能。这些数据 支持人类合成突变可能改变突触传播和可塑性的观念。到 确定与疾病相关的合成突变如何影响突触的病理生理学和行为，我们将 首先是Syngap疾病风险变异对突触结构和功能的影响 包括实时成像，生化和电生理技术在内的方法的组合。下一个， 我们将使用CRISPR/CAS9基因组编辑来生成携带syngap突变的鼠标模型 精确模仿人类疾病的风险变体。使用这些老鼠，我们将确定他们是否有 差异可塑性，电路和行为表型。最后，我们将执行基于机制的药物 筛选以靶向破坏合成调节的信号转导途径，以发现小分子 可以改善突触和行为缺陷。这个拟议的项目将是第一个系统的 研究突触病理生理学和动物行为的疾病相关的合成突变。 这些研究将使我们能够深入了解与Syngap相关疾病和铺路的机制 新型治疗策略的方式。