IGF-I Actions in Oligodendrocyte/Myelin Injury

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DESCRIPTION (provided by applicant): Oligodendrocyte loss and demyelination are often major consequences of disorders of central nervous system (CNS), including multiple sclerosis (MS), undernutrition and injury from hypoxia/ischemia and trauma. Prevention of oligodendrocyte death and promotion of remyelination, therefore, are crucial to the structural and functional recovery of the CNS from injury. Our recent data and the data of others indicate that insulin-like growth factor-1 (IGF-I) is capable of protecting oligodendrocytes and myelination against injury and promoting regeneration of myelin following injury. We hypothesize that IGF-I acts directly on the cells of oligodendrocyte lineage by mechanisms that are initiated by interaction with its cell surface receptor, the type 1 IGF receptor (IGF1R), and in turn by its regulation of gene expression. Our hypothesis is supported by the evidence that IGF-I promotes proliferation and differentiation of cultured oligodendrocyte lineage cells. Furthermore in rodents subjected to demyelinating insults, the expression of IGF-I and IGF1R genes is induced in a fashion temporally and spatially related to the injury. Our recent studies further support the hypothesis by showing that: a) IGF-I significantly promotes myelination during development, and b) our initial studies of mice carrying an IGF1R null deletion specifically in mature oligodendrocytes demonstrate that IGF-I actions are directly mediated by interactions with the IGF1R. In this application, we propose to define IGF direct actions on cells of the oligodendrocyte lineage in vivo. We will: a) generate two mutant mouse models, each with blunted IGF1R expression specifically in oligodendrocyte precursors or in mature oligodendrocytes, and b) in each model we will evaluate oligodendrocyte development and myelination during development and the response of oligodendrocyte lineage cells to cuprizone and to ischemia/hypoxic injury.