Multiple sclerosis (MS) is a debilitating neurologic disease of young adults characterized by central nervous system (CNS) lesions in which myelin sheaths and oligodendrocytes are selectively lost from large areas of white matter as a result of an immune-mediated process. An increasing number of reports on MS indicate that CNS is capable of some remyelination. This project builds on recent data suggesting that receptor molecules occur within the CNS during inflammation that may operate to the advantage of the tissue and facilitate myelin repair. For this, a battery of molecules will be examined that are involved in CNS inflammation, development, cell survival and myelin repair with a view to developing to developing a therapeutic approach. The hypothesis under test is that homeostasis in a normal white matter is regulated by receptor molecules at the blood-brain barrier, on the myelin/oligodendrocyte complex and on the axon. It is hypothesized that under normal circumstances, these receptors protect these elements from damage and that following inflammation-related injury, oligodendrocyte precursor and repair-related gene are induced or up-regulated as part of the response. The proposed approach will combine neuropathology, immunocytochemistry and neuroimmunology with CNS tissue from mice with an autoimmune demyelinating disease and from cases of human MS, and with glial cell and leukocyte cultures, to investigate the expression of molecules involved in leukocyte trafficking, oligodendrocyte regeneration, remyelination and axonal integrity.
Four specific aims are proposed. The first will examine the adhesion molecule/chemokine/cytokine profiles during experimental autoimmune encephalomyelitis (EAE) in mice lacking the chemokine receptor CCR2, a molecule that enables monocytes to recognize the chemokine MCP-1 and home to sites of inflammation. Pilot studies on CCR2-/- mice with EAE indicate that the CNS is infiltrated by unusually high numbers of neutrophils and that axon are remarkably spared.
The second aim i nvolves the treatment of mice with EAE with a neurotrophic molecule, glial growth factor 2, (GGF2), a molecule belonging to the neuregulin family of neutrophins that has recently been shown to induce amelioration of disease which is accompanied by axonal sparing, enhanced remyelination and a possible shift to a Th2-type cytokine profile. Mice with EAE treated with GGF2 will be examined for expression and localization of GGF2 and erbB2, erbB3 and erbB4 (receptors through which GGF2 signals), and the findings correlated with axonal pathology and remyelination.
The third aim will look at the expression of GGF2 and its receptors in MS and relate it to nerve fiber pathology and remyelination.
The third aim will look at the expression of GGF2 and its receptors in MS and relate it to nerve fiber pathology and the fourth will examine MS lesions of different ages for molecules believed to be expressed on precursor oligodendrocytes viz. PDGF-Ralpha and NG-2 and the findings interpreted against the degree of myelin repair. Pilot studies indicate all these experiments to be feasible and it is believed that the approach is highly significant for the MS patient in that it might level to novel therapeutic strategies.
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