Programmed cell death (PCD), a normal part of the development of many cell types, has recently been shown to occur in cells of the oligodendroglial lineage and can be prevented by protein growth factors. Preliminary data suggests that this cell death may occur at several stages of the oligodendroglial lineage, that many cells are eliminated by apoptosis, the most common method of programmed cell death characterized primarily by nuclear fragmentation, and that the growth factors which inhibit this death operate in a stage specific manner. Cell death also has been detected in several dysmyelinating mutations in rodents and following Wallerian degeneration of the optic nerve. They hypothesize that accentuation of programmed cell death in these pathologies is responsible for oligodendroglial depletion and that prevention of cell death by the appropriate growth factors could ameliorate these conditions. They will determine which stage(s) of development of the oligodenroglial lineage is most vulnerable to cell death, and whether apoptosis is increased during Wallerian degeneration and in the myelin deficient (MD) rat, and which growth factors most effectively inhibit programmed cell death both in vivo and in vitro. They will utilize an assay which detects nuclear fragmentation, can be combined with immunophenotyping, and works well both in vitro and in vivo.
Their specific aims are: 1. To examine cell death, the amount of apoptosis, and the stages of the oligodendroglial lineage at which apoptosis occurs in vitro using a well characterized rat cerebral white matter culture system. Then they will determine which growth factors best prevent this cell death; 2. To assess apoptotic cell death of oligodendroglial lineage cells in vivo.; 3. To test the hypothesis that the depletion of the oligodenroglial lineage cells following Wallerian degeneration is a consequence of oligodendrocyte precursor apoptosis caused by loss of axonal contact. They will also determine if this apoptosis can be inhibited by growth factors normally secreted by or presented on neurons; and 4. To ascertain if there is an increase in apoptosis in myelin deficient rats, at what stage of development apoptosis occurs, and if growth factors can decrease this cell death.
