TRANSFERRIN GENE REGULATION--ROLE IN MYELINATION AND INJURY RESPONSES

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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.