DYSLEXIA SUSCEPTIBILITY GENES AND MECHANISMS OF NEURONAL DEVELOPMENT

阅读障碍易感基因和神经元发育机制

• 批准号: 8053658
• 负责人: Joseph J LoTurco
• 金额: $ 0.84万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053658
• 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; cell motility; combinatorial; extracellular; functional disability; gain of function; gene function; in utero; migration; neocortical; neuron development; novel; overexpression; protein protein interaction; research study

DYSLEXIA SUSCEPTIBILITY GENES AND MECHANISMS OF NEURONAL DEVELOPMENT 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 popualtions, 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. 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.

阅读障碍的易感基因及其神经元机制 发展 阅读障碍(RD)或阅读障碍是儿童最常见的学习障碍。 虽然阅读障碍的具体原因尚不清楚，但最近的遗传和 神经生物学研究强化了阅读困难是由早期阅读障碍引起的工作假说。 随后导致新皮质功能障碍的发育障碍 电路。在过去的三年里，四个候选的阅读障碍易感基因 (DYX1C1、KIAA0319、DCDC2和Robo1)，所有四个都在 神经元发育。其中三个的啮齿动物同源物Dyx1c1，KIAA0319和 DCDC2已被证明在新皮质发育中的神经元迁移中发挥作用， 此前，Robo1被证明对轴突的生长和引导很重要。这个 该项目的前三个目标将进一步定义细胞和发育角色 KIAA0319和DCDC2是目前阅读障碍遗传支持最强的两个基因 易感基因。这三个目标是确定神经元的成分 受DCDC2和KIAA0319控制的迁移，以确定 KIAA0319和DCDC2在神经元迁移中的作用 DCDC2和KIAA0319的蛋白质结构域。这些目标将通过联合行动来实现 子宫内RNAi、成像和细胞培养方法。一种新的组合方法 RNAi和电穿孔技术用于研究KIAA0319和KIAA0319之间的相互作用 DCDC2。最后，与目前正在努力确定其他 阅读障碍的易感基因，我们建议测试发育 新的候选阅读障碍易感基因在神经元迁移和表达中的作用 发展。总之，这些实验的结果将揭示细胞的功能 候选阅读障碍易感基因在神经元发育中的作用，这应该 有助于最终了解这种学习障碍的根本原因。阅读障碍(RD)或阅读困难是儿童中最常见的学习障碍 孩子们。虽然阅读障碍的具体原因尚不清楚，但最近的遗传和 神经生物学研究强化了阅读困难是由早期阅读障碍引起的工作假说。 随后导致新皮质功能障碍的发育障碍 电路。这些拟议实验的结果将揭示细胞功能 神经元发育中的候选阅读障碍易感基因，这应该 有助于最终了解这种学习障碍的根本原因。