It is well established that prenatal exposure to ethanol has severe effects upon the developing nervous system, causing mental retardation, cognitive deficiencies and neuromuscular abnormalities. The Insulin-like growth factor 1-receptor (IGF-I-R) is vigorously expressed in the developing central nervous system and is thought to play a major role int he control of cell growth, both in terms of cell size and cell number. The cell line T98G, originating from a human glioma, can grow in SFM with only the addition of IGF-I. The addition of ethanol to the medium dramatically reduces the growth of T986 cells. If the cells are rendered quiescent, ethanol reduces the IGF-I mediated mitogenic response. T98G cells transfected with a human IGF-I-R expression plasmid (and therefore overexpressing IGF-I-R) are much more resistant to the effect of ethanol. It seems, therefore, that ethanol somehow affects the activity of the IGF-I-R. Because of the role that the IGF-I-R plays in cell growth and differentiation, including the nervous system, this study aims to analyze the mechanism(s) by which ethanol decreases the response to IGF-I in a cell of glial origin, a) investigate how an increase in the number of IGF-I-R results in a partial protection from the inhibitory effect of ethanol; b) determine the mechanism(s) of this inhibition, whether at the level of the receptor itself, at the gene expression level, or in the signal transducing pathway; c) determine the point in the cell cycle at which ethanol acts; d) determine if the ethanol-induced inhibition can be overcome by the use of certain growth factors; and e) study the effect of ethanol on the differentiation of neuroblastoma cells. These studies should shed considerable light on the mechanisms by which ethanol affects the development of cells in the central nervous system.
NIH ExPorter
NIH ExPorter