The current treatment of many neurologic disease processes such as Alzheimer~s Disease, Huntington~s Disease, Parkinson~s Disease, multiple sclerosis and stroke is clearly inadequate. A major problem has been that the underlying pathophysiology of these diseases and the underlying biology of the CNS, will the stage be set for the development of more effective treatments. The short-term goal of this project is to develop a better biological understanding of glial cell development. One of the critical issues in CNS development concerns the mechanisms of cellular diversity. The glial O-2A progenitor cell, for example, differentiates into an oligodendrocyte or an astrocyte, depending on the environmental conditions. The intracellular mechanisms that govern this process are unclear. Towards this goal, work has already been initiated on a model system to address glial cell development, the CG-4 glial precursor cell. This cell differentiates into an astrocyte or an oligodendrocyte, depending on the culture conditions. The cell cycle proteins,known to be important in regulating cellular proliferation, are being examined for their role in glial development. Preliminary data already indicate that one of the these proteins, p27kip, may be involved in the mechanism of astrocyte differentiation. Ultimately, we hope to determine the exact mechanisms ofthe cell cycle regulation in glial development, by utilizing biochemical, molecular biological, and cell biological approaches. To delineate the mechanisms by which the cell cycle proteins regulate glial cell development, we propose: 1. To determine the specific cell cycle mechanisms involved in astrocyte differentiation, 2. To determine the specific cell cycle mechanisms involved in oligodendrocyte differentiation, and 3. To identify the physiologic significance of p27 during astrocyte development.
