Molecular Mechanism of Neuronal Migration

描述(申请人提供)：尽管大脑皮层负责所有使我们成为人类的智力生活，但我们对这种令人惊叹的结构是如何形成的知之甚少。然而，我们确实知道，皮质没有正确形成的遗传条件会造成毁灭性的后果。神经疾病，如顽固性儿童癫痫，经常与发育性脑畸形有关。到目前为止，在了解这些疾病的病理基础方面取得的进展来自对皮质畸形动物模型的研究，以及对人类神经元迁移障碍的分子遗传学方法的研究。无脑畸形和脑室周围异位症是这样的人类神经元迁移障碍，在这些疾病中，Lies1和Fl1基因的突变导致皮质神经元迁移的严重缺陷。Lis1和Fl1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成分相互作用。我们已经鉴定出许多与Lis1和Fln1相互作用的蛋白。与Lis1相互作用的蛋白之一mNudE被认为是Lis1的S在微管调节和神经元迁移中所必需的。本研究计划的总体目标是了解LISI-mNudE相互作用和Fln1介导的神经元迁移的分子机制。特异性目的1是研究mNudE和Lis1-mNudE相互作用在皮质发育中的分子机制和生物学意义，特异性目的2是研究Fln1和FlN1介导的信号转导在皮质发育中的作用。实验方法的重点是建立小鼠模型来解决特定的目标。所提出的实验结果将把我们的知识从皮质神经元迁移的分子机制过渡到人脑的形成，并将为人类神经遗传疾病的发病机制提供重要的见解。该候选人有医学和生物医学背景，并在博士和博士后培训期间接受过分子方法的强化培训。她现在正在克里斯·沃尔什博士和大卫·奎特科夫斯基博士的指导下寻求进一步的老鼠遗传学和神经解剖学方面的培训。这些培训将极大地增强候选人进行独立科学研究的潜力。

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.