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DYSLEXIA SUSCEPTIBILITY GENES AND MECHANISMS OF NEURONAL DEVELOPMENT

阅读障碍易感基因和神经元发育机制

基本信息

批准号：
8013557
负责人：
Joseph J LoTurco
金额：
$ 30.9万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8013557
关键词：
Adhesions Affect Binding Cell Adhesion Cell Culture Techniques Cell physiology Child Collaborations Deletion Mutation Dendrites Development Dyslexia Electroporation Fiber Gene Targeting Genes Genetic Growth Homologous Gene Human Image Immigration Learning Disorders Link Methods Microtubules Neocortex Neurobiology Neurons Pathway interactions Phenotype Play Population Predisposition Process Protein Binding Domain Proteins RNA Interference Radial Reading Disabilities Rodent Role Sequence Analysis Signal Transduction Staging Susceptibility Gene Tertiary Protein Structure Testing Work axon growth axon guidance cell motility combinatorial extracellular functional disability gain of function gene function genetic analysis in utero migration neocortical neuron development novel overexpression protein protein interaction research study

项目摘要

DESCRIPTION (provided by applicant): Reading disability (RD) or dyslexia is the most common learning disorder in children. While the specific causes of dyslexia are not yet known, recent genetic and neurobiological studies strengthen a working hypothesis that dyslexia is caused by early developmental disruptions that subsequently cause functional impairments in neocortical circuits. Within the past three years four candidate dyslexia susceptibility genes have been proposed (DYX1C1, KIAA0319, DCDC2 and ROBO1), and all four play roles in neuronal development. Rodent homologs of three of these, Dyx1c1, Kiaa0319 and Dcdc2 have been shown to play a role in neuronal migration in developing neocortex, and Robo1 was previously shown to be important for axon growth and guidance. The first three aims of the project will further define the cellular and developmental roles of Kiaa0319 and Dcdc2, the two genes currently with strongest genetic support as dyslexia susceptibility genes. These three aims are to determine the components of neuronal migration regulated by dcdc2 and kiaa0319, to determine functional links between kiaa0319 and dcdc2 in neuronal migration, and to determine the functionally necessary protein domains of dcdc2 and kiaa0319. The aims will be carried out by a combination of in utero RNAi, imaging, and cell culture approaches. Novel combinatorial methods of RNAi and electroporation are proposed to investigate interaction between Kiaa0319 and Dcdc2. Finally, in collaboration with groups currently working on identifying additional dyslexia susceptibility genes in human populations, we propose to test the developmental roles of new candidate dyslexia susceptibility genes in neuronal migration and development. Together, results form these experiments will reveal the cellular functions of candidate dyslexia susceptibility genes in neuronal development, and this should contribute to an eventual understanding of the underlying causes of this learning disorder. Project Narrative: Reading disability (RD) or dyslexia is the most common learning disorder in children. While the specific causes of dyslexia are not yet known, recent genetic and neurobiological studies strengthen a working hypothesis that dyslexia is caused by early developmental disruptions that subsequently cause functional impairments in neocortical circuits. Results form these proposed experiments will reveal the cellular functions of candidate dyslexia susceptibility genes in neuronal development, and this should contribute to an eventual understanding of the underlying causes of this learning disorder.

描述（由申请人提供）：阅读障碍（RD）或诵读困难是儿童中最常见的学习障碍。虽然阅读障碍的具体原因尚不清楚，但最近的遗传学和神经生物学研究加强了一个工作假设，即阅读障碍是由早期发育中断引起的，随后导致新皮层回路的功能障碍。在过去的三年中，已经提出了四个候选的阅读障碍易感基因（DYX1C1，KIAA0319，DCDC 2和ROBO 1），并且所有四个都在神经元发育中发挥作用。其中三个的啮齿动物同源物Dyx1c1，Kiaa0319和Dcdc2已被证明在发育中的新皮层中的神经元迁移中发挥作用，Robo1先前被证明对轴突生长和指导很重要。该项目的前三个目标将进一步定义Kiaa0319和Dcdc2的细胞和发育作用，这两个基因目前作为阅读障碍易感基因具有最强的遗传支持。这三个目标是确定由dcdc2和kiaa0319调节的神经元迁移的组分，确定kiaa0319和dcdc2在神经元迁移中的功能联系，以及确定dcdc2和kiaa0319功能上必需的蛋白质结构域。这些目标将通过子宫内RNAi、成像和细胞培养方法的组合来实现。提出了RNAi和电穿孔相结合的新方法来研究Kiaa0319和Dcdc2之间的相互作用。最后，与目前正在确定其他阅读障碍易感基因的人群合作，我们建议测试新的候选阅读障碍易感基因在神经元迁移和发育中的作用。总之，这些实验的结果将揭示候选阅读障碍易感基因在神经元发育中的细胞功能，这将有助于最终了解这种学习障碍的根本原因。项目叙述：阅读障碍（RD）或诵读困难是儿童中最常见的学习障碍。虽然阅读障碍的具体原因尚不清楚，但最近的遗传学和神经生物学研究加强了一个工作假设，即阅读障碍是由早期发育中断引起的，随后导致新皮层回路的功能障碍。这些实验的结果将揭示候选阅读障碍易感基因在神经元发育中的细胞功能，这将有助于最终了解这种学习障碍的根本原因。