ROLE OF REELIN IN CONTROL OF CELL MIGRATION IN BRAIN

描述(摘自申请者摘要)：神经元迁移缺陷 在许多人类神经疾病中都有描述，包括 神经发育异常，儿童癫痫和精神分裂症。 此外，在治疗脑部疾病方面遇到的主要问题之一 肿瘤是指癌细胞在中枢扩散的能力。 神经系统。对小鼠共济失调突变的研究导致了 几个在细胞调控中起作用的基因的鉴定 在大脑发育过程中的定位。特别是，从 1995年鉴定了Reelin基因，它是信号的几个组成部分 已经发现了对层流形成至关重要的途径 结构。 这次竞争性续约是基于我们最初发现的Reelin和 在阐述Reelin的上一个资助期取得的进展 信号通路。Reelin是一种能与脂蛋白结合的大分泌蛋白。 受体并诱导失活蛋白1酪氨酸磷酸化和降解 (DAB-1)。此信号继电器用于拆分预制板和 皮质板的形成，浦肯野细胞的迁移和其他几个 大脑和脊髓中的细胞定位事件。 我们提出了一种多学科的方法来阐明分子和 由Reelin途径控制的生物事件。一种分子的组合 生物学、蛋白质生物化学、细胞生物学和整体动物研究 设计了三个协同的具体目标。第一个目标是关于 Reelin的提纯、性质及其相互作用 与脂蛋白受体和其他细胞表面或细胞外蛋白结合。 导致DAB-1磷酸化的细胞内信号事件和 DAB-1的后续功能将继续进行，利用该蛋白质 在上一个供资期间发现的相互作用。最后，转基因 小鼠、脑片培养和分离培养将被用来研究 Reelin信号通路组件在神经元中的功能作用。这 提案将产生有关负责机制的新信息 用于大脑发育和神经细胞功能。这些研究将有 对几种病理情况的重要影响，包括儿科 癫痫、精神分裂症和阿尔茨海默病。

DESCRIPTION (From the Applicant's Abstract): Neuronal migration defects have been described in many human neurological disorders, including neurodevelopmental abnormalities, pediatric epilepsy and schizophrenia. Furthermore, one of the major problems encountered in the treatment of brain tumors is the ability of cancer cells to disseminate throughout the central nervous system. The study of ataxic mutations in mice has led to the identification of several genes that function in the control of cell positioning during brain development. In particular, starting with the identification of the Reelin gene in 1995, several components of a signaling pathway have been uncovered that are critical for the formation of laminar structures. This competitive renewal is based on our initial discovery of Reelin and the advances made in the previous funding period that elaborated the Reelin signaling pathway. Reelin is a large secreted protein that binds to lipoprotein receptors and induces tyrosine phosphorylation and degradation of Disabled-1 (Dab-1). This signal relay is required for splitting of the preplate and formation of the cortical plate, migration of Purkinje cells and several other cell positioning events in the brain and spinal cord. We propose a multidisciplinary approach to elucidation of the molecular and biological events controlled by the Reelin pathway. A combination of molecular biology, protein biochemistry, cell biology and whole animal studies have been designed in three synergistic specific aims. The first aim concerns the purification and characterization of Reelin with an emphasis on its interaction with lipoprotein receptors and other cell surface or extracellular proteins. Intracellular signaling events leading to phosphorylation of Dab-1 and the subsequent function of Dab-1 will be pursued, taking advantage of the protein interactions uncovered in the previous funding period. Finally, transgenic mice, brain slice cultures and dissociated cultures will be used to study the functional roles of components of the Reelin signaling pathway in neurons. This proposal will generate new information concerning the mechanisms responsible for brain development and nerve cell function. These studies will have important implications for several pathological conditions, including pediatric epilepsy, schizophrenia and Alzheimer's disease.