Analysis of the Exon Junction Complex in Neural Development and Microcephaly

神经发育和小头畸形中外显子连接复合体的分析

• 批准号: 8197813
• 负责人: Debra Silver
• 金额: $ 24.41万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197813
• 关键词: Academic Medical Centers; Accounting; Address; Affect; Binding; Biological; Brain; Brain Stem; Cell Maintenance; Cell division; Cell physiology; Cells; Centrosome; Cerebral cortex; Chromosomes; Clinical; Complex; Data; Defect; Development; Development Plans; Diagnostic; Disease; Embryology; Etiology; Exons; Foundations; Future; Genes; Genetic; Genome Stability; Goals; Grant; Hela Cells; Hereditary Disease; Instruction; Knowledge; Mental Retardation; Microcephaly; Mitosis; Mitotic spindle; Modeling; Mus; Mutant Strains Mice; Mutation; National Human Genome Research Institute; Neocortex; Neurodegenerative Disorders; Neurons; Nonsense-Mediated Decay; Organ; Phase; Phenotype; Population; Positioning Attribute; Process; Production; Proteins; RNA; RNA Binding; RNA Splicing; RNA-Binding Proteins; Rare Diseases; Regulation; Research Personnel; Research Proposals; Role; Stem cells; Syndrome; Testing; Therapeutic; Training; Translations; United States National Institutes of Health; Ventricular; base; brain size; career; career development; genetic pedigree; insight; mouse model; mutant; nerve stem cell; neurodevelopment; neurogenesis; neuron apoptosis; novel; stem cell division; stem cell population; success

The objectives of this career development proposal are first to expand the Pi's training in neural development and second, to understand why mutation ofan RNA-binding complex component causes reduced brain size. Towards the first objective we have formulated a career development plan to provide necessary scientific and career training for the PI to achieve success as an independent investigator. The training for the K99 phase took place at NHGRI on the NIH campus. For the ROO phase of the proposal, the research will be carried out at Duke University Medical Center. Integral to this training is a panel of advisors that bring together expertise in mouse embryology, neural development, microcephaly, and mitosis. Towards the second objective we will continue our study of a new mouse model of microcephaly we have identified called Mos2. Microcephaly is a genetic disorder in which brain size is significantly reduced resulting in mental retardation. It has been proposed that microcephaly is caused by defects in neural stem cell division in the developing neocortex. There is a need for additional models to further validate this concept. Our initial characterization of Mos2 mutants indicates that neural stem cell function is compromised in these mice due to mutation in a component of the exon junction complex, an RNA-binding complex not previously implicated in neural development. In this proposal we will test the hypothesis that this complex is required for neural stem cell maintenance by regulating asymmetric cell division. In the K99 phase, we characterized the neural stem cell and differentiated neuronal populations in Mos2 mutants to evaluate how neural stem cell function is disrupted. In the ROO phase we will use cell biological and genetic approaches to ask if other components of the exon junction complex regulate brain size and stem cell division. This proposal will provide insight into regulation of neural development, the mechanism of microcephaly and other neurodevelopmental diseases, and specifically address the role of RNA binding proteins in these processes. Pursuing these aims will provide the necessary foundation for a career as an independent investigator in neural development.

该职业发展提案的目标首先是扩大 Pi 的神经网络培训 其次，了解为什么 RNA 结合复合物成分的突变会导致 大脑尺寸缩小。为了实现第一个目标，我们制定了职业发展计划，以提供 PI 必须接受必要的科学和职业培训，以取得作为独立研究者的成功。这 K99 阶段的培训在 NIH 校区的 NHGRI 进行。对于提案的原产地规则阶段， 研究将在杜克大学医学中心进行。本次培训的组成部分是顾问小组 汇集了小鼠胚胎学、神经发育、小头畸形和有丝分裂方面的专业知识。 为了实现第二个目标，我们将继续研究我们拥有的新的小头畸形小鼠模型 鉴定为Mos2。小头畸形是一种大脑尺寸显着缩小的遗传性疾病 导致智力低下。有人提出小头畸形是由神经干缺陷引起的 发育中的新皮质的细胞分裂。需要额外的模型来进一步验证这一点 概念。我们对 Mos2 突变体的初步表征表明神经干细胞功能受到损害 在这些小鼠中，由于外显子连接复合物的一个组成部分发生突变，RNA结合复合物不 以前与神经发育有关。在这个提案中，我们将测试这个复合体的假设 通过调节不对称细胞分裂维持神经干细胞所需。在K99阶段，我们 表征了 Mos2 突变体中的神经干细胞和分化的神经元群体，以评估如何 神经干细胞功能被破坏。在 ROO 阶段，我们将使用细胞生物学和遗传学方法 询问外显子连接复合物的其他成分是否调节大脑大小和干细胞分裂。这 该提案将深入了解神经发育的调节、小头畸形的机制和其他 神经发育疾病，并特别强调 RNA 结合蛋白在这些过程中的作用。 追求这些目标将为作为独立调查员的职业生涯提供必要的基础 神经发育。