The Central Nervous System (CNS) is a primary target of biological aging, from a loss of neurons to decreased brain function, all the way to devastating diseases like Alzheimer's Disease (ALD). The IGF system (especially the IGF-I receptor, activated by its ligands) is known to play a significant role in mitogenesis, differentiation and protection from apoptosis (survival). All these functions of the IGF system are active during the development of the CNS, with the last two, differentiation and survival, becoming more prominent in adult life and aging. Aging in both sexes and menopause in women are also accompanied by a decrease in IGF-I levels in the plasma. Although the literature on the IGF system and the CNS is by now abundant, the present proposal aims at a different target, specifically the mechanism(s) by which the IGF-I receptor (IGF-IR) regulates the differentiation and/or survival of neurons (with the IR only involved in survival). The main model system is based on a neuronal cell line, immortalized by a temperature-sensitive SV40 T antigen. These cells, designated as H19-7 cells, grow quite well in growth medium at the permissive temperature of 340, but they growth-arrest, and differentiate when incubated with bFGF, at the restrictive temperature of 39o. Our preliminary results indicate that, in the presence of IGF-I, a modestly over-expressed IGF-I receptor can induce differentiation, in the absence of any other growth factor. We can therefore carry out in this cell line a mutational analysis of the IGF-IF in differentiation and survival (as we have already done for mitogenesis and transformation), which will provide us with the basic information to elucidate the pathway(s) involved in these processes. Finally, we have recently developed neuronal (and fibroblastic) cell lines from mice homozygous for targeted disruptions of both the IGF-IR and IGF-II receptor genes. These cell lines (also immortalized by a tsA SV40 T antigen) will be extremely useful in elucidating insulin receptor signaling in cell survival.
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