DESCRIPTION (from the application): The molecular mechanisms governing the decision of dividing neural progenitor cells to exit the cell cycle and differentiate into mature nondividing cells, such as neurons and oligodendrocytes, are incompletely understood. Shortening of the specialized ends of chromosomes, called telomeres, has been proposed as a means used by cells to monitor and limit their number of cell divisions. The ribonucleoprotein DNA polymerase telomerase is important for maintenance of telomeric length and integrity. Differentiation of several immortalized cell lines, including leukemic cells, teratocarcinoma, and pheochromocytorna cells, is associated with loss of telomerase activity and shortening of telomeres. It is not known how telomerase activity, regulation of telomere length, and differentiation are coupled, but DNA checkpoint control and activation of cellcycle suppressor molecules have been implicated. The role of telomeres and telomerase in the proliferation and differentiation of progenitor cells in the brain will be examined. The levels of telomerase in primary cultures of neural progenitor cells before and after differentiation will be investigated by activity assays, immunoblotting, and microscopy. Subsequent studies will employ biochemical methods to examine telomere length and shortening and the regulation of telomerase levels. Transgenic mice and protein transduction experiments will attempt to demonstrate a causal role for telomerase in neural proliferation and differentiation. In addition to contributing to an understanding of the regulatory mechanisms of neurogenesis and gliogenesis in the mammalian brain, such studies would be useful in exploring the ability of the brain to replace cells lost during aging, neurodegenerative diseases. and stroke and in designing therapies to treat these maladies.