Functional Characterization of a Causative Gene for Intellectual Disability

智力障碍致病基因的功能表征

基本信息

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
项目类别：
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

项目摘要

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了 1-3% 的美国人口。相关神经系统疾病包括自闭症、科芬-西里斯综合症、米勒-迪克综合症、唐氏综合症、脆弱症。 X 综合征、胎儿酒精谱系障碍和小头畸形这种残疾会在儿童时期出现，并导致学习和掌握重要日常技能的障碍。这是一个终生问题，影响成本。尽管智力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，目前尚不存在富含 AT 的相互作用域蛋白 1B (ARID1B)。 SWI/SNF 染色质重塑复合体的成员，已被确定为多种与智力障碍和自闭症相关的综合征和非综合征的致病因素，然而，该基因在大脑发育过程中的神经功能是不同的。该提案的目的是确定 ARID1B 在神经发育中的作用，并建立智力障碍动物模型。我们的初步数据表明，ARID1B 在哺乳动物发育过程中径向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，我们结合小鼠遗传学和分子/生物化学发现，ARID1B 功能的丧失会破坏发育中大脑的正常神经迁移和树突/突触发育。方法，我们将通过检查以下相关目标来检验这一假设：目标 1) 确定 ARID1B 在发育中的大脑中细胞类型特异性定位和迁移的要求；目标 2) 定义 ARID1B 在树突形态发生和突触可塑性中的作用目标 3) 表征 ARID1B 敲除小鼠的行为表型；目标 4) 确定是否增强 TrkB/PI3K 信号传导这项研究有望挽救由 ARID1B 基因缺失引起的神经缺陷，并为这种疾病的致病机制提供新的见解，并建立适当的动物模型。此外，这项研究的结果将作为开发治疗的基础。智力障碍的策略。