ROLE OF REELIN IN CONTROL OF CELL MIGRATION IN BRAIN

描述（来自申请人的摘要）：神经元迁移缺陷具有 在许多人类神经系统疾病中被描述，包括 神经发育异常，小儿癫痫和精神分裂症。 此外，在治疗脑梗塞中遇到的主要问题之一是， 肿瘤是癌细胞扩散到整个中央的能力。 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基因的鉴定 大脑发育过程中的定位。特别是，从 1995年，Reelin基因的鉴定， 已经发现的路径是形成层流的关键 结构. 这次有竞争力的更新是基于我们对Reelin的最初发现， 上一个供资期的预付款， 信号通路Reelin是一种与脂蛋白结合的大分泌蛋白 受体并诱导Disabled-1的酪氨酸磷酸化和降解 （Dab-1）。该信号继电器用于预板的分裂， 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。 我们提出了一个多学科的方法来阐明的分子和 由Reelin途径控制的生物事件。分子的组合 生物学、蛋白质生物化学、细胞生物学和整个动物研究已经 三个协同的具体目标。第一个目标涉及 分离纯化并鉴定了Reelin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质结合。 导致Dab-1磷酸化的细胞内信号传导事件和 Dab-1的后续功能将利用蛋白质 在上一个供资期间发现的互动。最后，转基因 小鼠、脑切片培养物和分离培养物将用于研究 Reelin信号通路的组成部分在神经元中的功能作用。这 建议将产生有关负责机制的新信息， 促进大脑发育和神经细胞功能。这些研究将 对几种病理状况的重要影响，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.