Multiple sclerosis (MS) is an autoimmune CNS disease characterized by chronic progressive demyelination and the failure of adequate remyelination. The focus of the research in our laboratory is to determine how oligodendrocyte development and myelination are regulated, with the goal of understanding the basic process of myelination and obtaining the basic information required to design therapies to promote remyelination of MS. We have shown previously that the insulin-like growth factors (IGF-I and IGF-II are potent regulators of oligodendrocyte development and myelination. In prior work in our laboratory, we have shown that IGF-I and IGF-II act as mitogens for oligodendrocyte progenitors, as differentiation factors that induce uncommitted glial precursors to develop into oligodendrocytes, and as regulators of the production of myelin components in differentiated oligodendrocytes. As a result, IGFs increase the number of oligodendrocytes that develop in vitro by as much as 60-fold, regulate the amount of myelin that is synthesized in vitro and in vivo and promote oligodendrocyte regeneration. We now propose to investigate several key questions that are important both for a sound basic understanding of IGF regulation of oligodendrocyte development and for the application of this information to clinical problems.
In specific aim 1, purified populations of developing oligodendroglial cells will be analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR) and RNase protection assay to detect autocrine synthesis of IGF-I or IGF-II mRNA, and will be exposed to IGF blockers to determine whether oligodendrocyte development is regulated, in part, by autocrine production of IGFs, as suggested by prior studies. In our second specific aim, we will analyze the interactions between the IGFs and two other important regulators of oligodendrocyte development, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), in promoting oligodendroglial cell proliferation and differentiation, and will use IGF blockers and methods of molecular biology to detect whether PDGF, FGF and/or EGF affect oligodendrocyte development, in part, by activation of an autocrine loop based on IGF production. Third, we will precisely define the stages during oligodendrocyte development when IGFs exert each of their different effects on development, as must be known before IGF-I-based therapy can be contemplated. Fourth, we will use RT-PCR, RNase protection assay and other methodologies to investigate expression by astrocytes and developing oligodendrocytes of IGF binding proteins (IGFBPs), which are known to profoundly affect IGF action but whose contribution to oligodendrocyte development is completely unknown. In our fifth specific aim, we will use methodologies of cDNA subtraction cloning to screen for genes whose expression is either up-regulated or down-regulated during the process of IGF-induced oligodendrocyte development, to gain insight into the molecular mechanisms of IGF-induced development. These studies will give important new insight into the regulation of oligodendrocyte development and myelination that will have both basic and clinical significance.
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