Functional Characterization of a Causative Gene for Intellectual Disability

智力障碍致病基因的功能表征

• 批准号: 9015785
• 负责人: Woo-Yang Kim
• 金额: $ 34.25万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9015785
• 关键词: ARID Domain; Adaptive Behaviors; Affect; Animal Model; Area; Autistic Disorder; Behavioral; Biochemical; Brain; Cerebral cortex; Childhood; Chromatin Remodeling Factor; Coffin-Siris Syndrome; Cognition; DNA Sequence Alteration; Data; Defect; Dendritic Spines; Development; Developmental Process; Disease; Down Syndrome; Education; Electrophysiology (science); Employment; Equilibrium; Etiology; Fetal Alcohol Spectrum Disorder; Fragile X Syndrome; Gene Deletion; Generations; Genes; Genetic; Genetic study; Goals; Health; Hippocampus (Brain); Immigration; Impairment; Intellectual functioning disability; Interneurons; Intervention; Knockout Mice; Lead; Learning; Life; Mediating; Memory; Methodology; Microcephaly; Microscopy; Miller-Dieker Syndrome; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Neurobiology; Neurologic; Neurons; Neuropathogenesis; Neurophysiology - biologic function; Outcome Study; Pathogenesis; Pathology; Phenotype; Play; Population; Positioning Attribute; Prevention strategy; Proteins; Publications; Role; Short-Term Memory; Signal Transduction; Slice; Social Interaction; Source; Structure; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; United States; base; behavioral impairment; cell type; cognitive function; cognitive process; cognitive skill; cost; developmental disease; disability; excitatory neuron; experience; gene therapy; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; knock-down; member; migration; neuron development; novel; relating to nervous system; skills; small hairpin RNA; treatment strategy; two-photon

 DESCRIPTION (provided by applicant): Intellectual disability that limits normal cognitive functioning and skill learning affects 1-3% of the population of the United States. Associated neurological conditions include autism, Coffin-Siris Syndrome, Miller-Dieker syndrome, Down Syndrome, Fragile X syndrome, Fetal Alcohol Spectrum Disorder, and microcephaly. This disability appears during childhood and leads to impairments in learning and acquisition of critical daily skills. This is a life-long problem, affecting the cost of long-term education and employment. Although intellectual disability is a clinically important disorder, the etiology and pathogenesis are poorly understood. Accordingly, pharmacological or genetic intervention does not currently exist. Recently, AT-rich interactive domain containing protein 1B (ARID1B), a member of SWI/SNF chromatin remodeling complex, has been identified as a causative factor for a several syndromic and nonsyndromic conditions associated with intellectual disability and autism. However, the neural function of this gene during brain development is unknown. The goal of this proposal is to define the role of ARID1B in neuronal development and establish an animal model for intellectual disability. Our preliminary data revealed that ARID1B plays important roles in positioning and differentiation of radially-migrating excitatory pyramidal neurons in the mammalian developing brain. Based on our preliminary results, we hypothesize that loss of ARID1B functions disrupts normal neuronal migration and dendritic/synaptic development in the developing brain. Using a combination of mouse genetics and molecular/biochemical approaches, we will test this hypothesis by examining the following related aims: Aim 1) Determine the requirement of ARID1B in cell-type- specific positioning and migration in the developing brain; Aim 2) Define the role of ARID1B in dendritic morphogenesis and synaptic plasticity in the developing brain; Aim 3) Characterize behavioral phenotypes of ARID1B knockout mice; and Aim 4) Determine if reinforcing TrkB/PI3K signaling rescues neuronal defects caused by ARID1B gene deletion. This study is expected to provide novel insights into the pathogenic mechanisms of intellectual disability, and establish an appropriate animal model for this condition. Furthermore, the outcome of this study will serve as a basis for developing treatment strategies for intellectual disability.

 描述(由申请人提供)：限制正常认知功能和技能学习的智力障碍影响到美国1-3%的人口。相关的神经系统疾病包括自闭症、棺材-西里斯综合征、米勒-迪克综合征、唐氏综合征、脆性X综合征、胎儿酒精谱系障碍和小头畸形。这种残疾出现在儿童时期，并导致学习和获得关键日常技能方面的障碍。这是一个终生的问题，影响着长期教育和就业的成本。虽然智能障碍是一种临床上重要的疾病，但其病因和发病机制尚不清楚。因此，目前还不存在药物或遗传干预。最近，富含AT的相互作用域包含蛋白1B(ARID1B)是SWI/SNF染色质重塑复合体的成员，已被确定为与智能障碍和自闭症相关的几种综合征和非综合征条件的致病因素。然而，该基因在大脑发育过程中的神经功能尚不清楚。这项提议的目标是确定ARID1B在神经元发育中的作用，并建立一个智力残疾的动物模型。我们的初步数据显示，ARID1B在哺乳动物发育中大脑中放射状迁移的兴奋性锥体神经元的定位和分化中发挥着重要作用。根据我们的初步结果，我们假设ARID1B功能的丧失扰乱了发育中大脑中正常的神经元迁移和树突/突触的发育。利用小鼠遗传学和分子/生化方法，我们将通过检验以下相关目的来检验这一假说：目的1)确定ARID1B在发育中的脑中特定细胞类型的定位和迁移中的需求；目的2)确定ARID1B在发育中的脑树突状细胞形态发生和突触可塑性中的作用；目的3)表征ARID1B基因敲除小鼠的行为表型；以及目的4)确定增强TrkB/PI3K信号是否可以挽救因ARID1B基因缺失而导致的神经元缺陷。这项研究有望为智能障碍的发病机制提供新的见解，并为这种疾病建立合适的动物模型。此外，这项研究的结果将作为制定智力残疾治疗战略的基础。