The overall goal of this proposal is to study the lipoprotein-mediated transport of lipids in regenerating nerve. The model to be examined is the transport of cholesterol and fatty acids by macrophages in degenerating peripheral nerve in the form of apolipoprotein E-containing particles to myelinating Schwann cells. This system will be used to test whether lipid reutilization is a prerequisite for successful nerve regeneration. To test this first hypothesis, the investigator will examine regeneration of peripheral nerve in mice that have received bone marrow transplants from mice in which macrophages are unable to process degenerating myelin. He will also use experimental in vivo delivery of substances to block the transport and cellular processing of cholesterol. In the second Specific Aim, he will attempt to identify the specific apolipoprotein and lipoprotein receptors involved in the uptake of myelin cholesterol by myelinating Schwann cells during regeneration. He will examine the expression of genes for lipoprotein receptors in regenerating nerve and determine if this is localized to Schwann cells. He will also utilize knockout mice deficient in specific lipoprotein receptors, to test the ability of peripheral nerve to regenerate and remyelinate in the absence of these receptors. Finally, he will utilize Schwann cell and dorsal root ganglion culture systems to investigate the function of apolipoproteins and their receptors in myelination.
| Goodrum, J F; Brown, J C; Fowler, K A et al. (2000) Axonal regeneration, but not myelination, is partially dependent on local cholesterol reutilization in regenerating nerve. J Neuropathol Exp Neurol 59:1002-10 |
| Goodrum, J F; Fowler, K A; Hostettler, J D et al. (2000) Peripheral nerve regeneration and cholesterol reutilization are normal in the low-density lipoprotein receptor knockout mouse. J Neurosci Res 59:581-6 |
