TRANSFERRIN GENE REGULATION--ROLE IN MYELINATION AND INJURY RESPONSES

神经生物学研究的成功取决于 适合研究复杂问题的简单系统。损伤 中枢神经系统的反应显然涉及一个复杂的和相互作用的链， 影响多种细胞类型的事件。在中枢神经系统中， 少突胶质细胞执行两个重要功能， 生物体在整个生命过程中的发育和生存能力。这两 功能是髓鞘形成和铁稳态。我们之前的研究表明 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。 少突胶质细胞的可塑性，主要是在体外和体内发现的， 在过去的15年里，体内研究使我们能够考虑 未探索的一般方面的调制所造成的伤害， 破坏铁的体内平衡。少突胶质细胞合成和分泌 转铁蛋白，一种铁转运糖蛋白，作为营养和 CNS中各种细胞类型的存活因子， 自分泌分化因子可能影响 髓鞘形成/髓鞘再生过程。在此，我们建议进一步 用免疫荧光技术研究大鼠转铁蛋白基因的调控区， 体外和转基因研究。已经证明了 TF进入成熟的少突胶质细胞的细胞核（但不进入其他 神经细胞），我们建议阐明其假定的作用， 转录因子我们将研究其中涉及的机制 现象，并确定推定的靶基因。对这些问题的解释 问题将提供新的见解调制损伤反应。 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 通过祖细胞移植该系统允许移植的细胞 在宿主薄壁组织内迁移、整合和髓鞘化。我们提出 建立和表征人类少突胶质细胞，并使用我们的 移植系统来研究它们在嫁接时的行为。我们觉得 这些多学科的研究将有助于更好地 了解神经胶质、中枢神经系统损伤和修复。60多名继承人 白色物质障碍已经被确定，并且许多与 智力迟钝和炎症。此外，缺铁是一种 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 可用于开发新模式的基本知识， 模拟CNS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.