The regulatory mechanisms by which Schwann cells control the expression oif myelin specific glycoconjugates will be evaluated in the presence and absence of myelin assembly and during various levels of Schwann cell differentiation in the following rat sciatic nerve models: neonatal, neonatal after tissue culture, normal adult, crushed adult, and transected adult.
The specific aims of this research plan include 1) control of PO gene expression: to correlate PO mRNA biosynthesis and steady state levels with the in vitro cell-free translation and in vivo biosynthesis of PO to determine if the control is at the transcription, translation, and/or post-translation levels in these models; 2) molecular sorting and intracellular targeting of PO: to quantitate PO biosynthesis in the transected nerve in the presence of lysosomotropic agents, to determine the route of PO targeting to the lysosome by Schwann cells in the transected nerve, and to ascertain the sorting signal on PO responsible for the lysosomal delivery; 3) induction of PO translation in neonatal Schwann cells after co-culture: to evaluate the mechanisms associated with the translational control of PO mRNA in cultured neonatal Schwann cells; and 4) alterations in glycolipid biosynthesis by Schwann cells: to further examine the mechanisms of control associated with the biosynthetic shift from the galactocerebrosides and monogalactosyl diacylglycerol during myelin assembly and maintenance to the glucocerebrosides and oligohexosylceramides in the absence of myelin assembly. It is anticipated that this approach will improve our understanding of the molecular michanisms associated with the initiation of the myelinating process. In addition, information concerning the regulatory events associated with myelination should prove useful for understanding human disease involving, for example, the inflammatory demyelinating peripheral neuropathies.
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