TRANSFERRIN GENE REGULATION--ROLE IN MYELINATION AND INJURY RESPONSES

神经生物学研究的成功取决于能否获得 适用于研究复杂问题的简单系统。伤害 中枢神经系统的反应显然涉及一条复杂和互动的链 影响多种单元格类型的事件。在中枢神经系统， 少突胶质细胞执行两个主要功能，对正常 整个生命中有机体的发育和生存能力。这两个 其功能是髓鞘形成和铁稳态。我们之前的工作表明 少突胶质细胞对环境变化高度敏感 使他们极易受到各种形式的伤害或疾病的伤害。 少突胶质细胞的可塑性，在体外和在 过去15年的活体研究，让我们还可以考虑 未探索的一般方面的调制所造成的伤害 打乱了铁的稳态。少突胶质细胞合成和分泌 转铁蛋白，一种铁运输糖蛋白，起到营养和 中枢神经系统中各种细胞类型的存活因子，以及作为 自分泌分化因子可能影响 髓鞘形成/再髓鞘形成过程。在此，我们建议进一步 用IN法研究大鼠转铁蛋白基因的调控区 体外和转基因研究。在证明了移位 Tf进入成熟少突胶质细胞的核(但不是其他 神经细胞)，我们建议阐明其作为一种 转录因子。我们将研究与此相关的机制。 现象，并确定可能的靶基因。对这些问题的解释 这些问题将为损伤反应的调节提供新的见解。 我们建议研究中枢神经系统的修复，特别是髓鞘再生的过程。 通过使用祖细胞移植。这个系统允许移植的细胞 在宿主实质内迁移、整合和髓鞘形成。我们建议 建立和鉴定人少突胶质细胞并使用我们的 移植系统，研究它们在嫁接后的行为。我们觉得 这些多学科研究将有助于更好地 了解神经胶质细胞、中枢神经系统的损伤和修复。超过60人继承 白质障碍已被发现，其中许多与 智力低下和发炎。此外，缺铁是一种 世界上影响髓鞘形成并导致 发育和认知功能障碍。这些研究将提供 可应用于开发新模式的基础知识 模拟中枢神经系统再生。

The success of neurobiological research depends upon the availability of suitable simple systems for the study of complex problems. Injury response in the CNS clearly involves a complex and interactive chain of events which impact upon multiple cell types. In the CNS, oligodendrocytes perform two major functions critical for proper development and viability of the organism throughout life. These two functions are myelination and iron homeostasis. Our previous work showed that oligodendrocytes are highly sensitive to environmental changes that make them extremely vulnerable to various forms of injury or diseases. Oligodendrocyte's plasticity, discovered largely in vitro as well as in vivo studies during the last 15 years, allows us to consider yet unexplored general aspects of the modulation of the injury caused by the disruption of iron homeostasis. Oligodendrocytes synthesize and secrete transferrin, an iron transport glycoprotein, that acts as a trophic and survival factor for the various cell types in the CNS, and as an autocrine differentiation actor that may affect the myelination/remyelination process. Here, we propose to further investigate the regulatory region of the rat Tf gene by means of in vitro and transgenic studies. Having demonstrated the translocation of Tf into the nucleus of maturing oligodendrocytes (but not of other neural cells), we propose to elucidate its putative role as a transcription factor. We will examine the mechanisms involved in this phenomenon, and identify putative target genes. The elucidation of these issues will provide new insights on the modulation of injury response. We propose to study CNS repair particularly the process of remyelination by using progenitor cell grafting. This system allows grafted cells to migrate, integrate and myelinate within the host parenchyma. We propose to establish and characterize human oligodendrocytes and use our transplantation system to study their behavior upon grafting. We feel that these multi-disciplinary studies will contribute to a better understanding of glia, CNS injury and repair. More than sixty inherited white matter disorders have been identified and many are associated with mental retardation and inflammation. Furthermore, iron deficiency is a major problem in the world that affects myelination and results in developmental and cognitive dysfunction. These studies will provide fundamental knowledge that can be applied to develop new modalities to simulate CNS regeneration.