Molecular Mechanism of Neuronal Migration

神经元迁移的分子机制

• 批准号: 6572469
• 负责人: Yuanyi Feng
• 金额: $ 15.47万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-06 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6572469
• 关键词: biological signal transduction; cell migration; cell proliferation; cerebral cortex; cytoskeleton; developmental neurobiology; embryonic stem cell; frameshift mutation; functional /structural genomics; gene deletion mutation; gene interaction; gene targeting; genetically modified animals; integrase; laboratory mouse; neurogenesis; neurogenetics; thymidine; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): Although the cerebral cortex is responsible for all the intellectual life that makes us human, we know remarkably little about how this amazing structure is formed. We do know, however, that genetic conditions in which the cortex is not formed properly have devastating consequences. Neurological disorders, such as intractable pediatric epilepsy, are frequently associated with developmental brain malformations. Progress toward understanding the pathologic basis of these diseases has so far come from research on animal models of cortical malformation and from molecular genetic approaches to human neuronal migration disorders. Lissencephaly and Periventricular Heterotopia are such human neuronal migration disorders in which mutations in LIS1 and FLN1 genes result in severe defects in cortical neuronal migration. Both LIS1 and FLN1 have been suggested to regulate cytoskeleton and both interact with other key components in the neuronal migration signaling pathways. We have identified many LIS1 and FLN1 interacting proteins. One of the LIS1 interacting proteins, mNudE, was suggested to be essential for LIS1's function in microtubule regulation and neuronal migration. The overall goal of this research proposal is aimed at understanding the molecular mechanism of neuronal migration mediated by LISI-mNudE interaction and by FLN1. Specific aim 1 is to investigate the molecular mechanism and biological significance of mNudE and LIS1-mNudE interaction in cortical development, while specific aim 2 is to study the function of FLN1 and FLN1 mediated signal transduction in cortical development. Experimental approaches are focused on establishing mouse models to address the specific aims. Results from proposed experiments will bridge our knowledge from molecular mechanism of cortical neuronal migration to the formation of human brain, and will also provide important insight into the pathogenesis of human neurogenetic disorders. The candidate had a background in medicine and biomedical science, and has had intensive training in molecular approaches during Ph.D. and postdoctoral training. She now seeks further training in mouse genetics and neuroanatomy under the mentorship of Drs. Chris Walsh and David Kwaitkowski. These training will greatly enhance the candidate's potential in conducting independent scientific research.

描述（由申请人提供）：虽然大脑皮层负责使我们成为人类的所有智力生活，但我们对这个惊人的结构是如何形成的知之甚少。然而，我们确实知道，大脑皮层不能正常形成的遗传条件会产生毁灭性的后果。神经系统疾病，如难治性小儿癫痫，经常与发育性脑畸形有关。迄今为止，对这些疾病的病理基础的理解进展来自于对皮质畸形动物模型的研究和对人类神经元迁移障碍的分子遗传学方法。无脑畸形和脑室周围异位是这样的人类神经元迁移障碍，其中LIS 1和FLN 1基因突变导致皮质神经元迁移的严重缺陷。LIS 1和FLN 1都被认为调节细胞骨架，并且都与神经元迁移信号通路中的其他关键组分相互作用。我们已经鉴定了许多LIS 1和FLN 1相互作用的蛋白。LIS 1相互作用蛋白之一mNudE被认为是LIS 1在微管调节和神经元迁移中的功能所必需的。本研究提案的总体目标是了解LISI-mNudE相互作用和FLN 1介导的神经元迁移的分子机制。具体目标1是研究mNudE和LIS 1-mNudE相互作用在皮质发育中的分子机制和生物学意义，具体目标2是研究FLN 1及其介导的信号转导在皮质发育中的作用。实验方法集中于建立小鼠模型以解决特定目标。实验结果将为我们从皮层神经元迁移的分子机制到人脑形成的认识架起一座桥梁，也将为人类神经遗传性疾病的发病机制提供重要的见解。 该候选人具有医学和生物医学科学背景，并在博士期间接受了分子方法的强化培训。和博士后培训。她现在在克里斯沃尔什和大卫奎特科夫斯基博士的指导下寻求进一步的小鼠遗传学和神经解剖学培训。这些培训将大大提高候选人进行独立科学研究的潜力。