Intrauterine growth retardation is known to affect the immediate and long term neurological outcome of the infant. However, many of the humoral factors involved in growth control and successful neurological development remain incompletely understood both in terms of factor identity and mechanism of action. A classic example of this is insulin which has been repeatedly shown to promote the proliferation and differentiation of many tissues, including neurons, and to possess the capacity of altering the feeding (satiety) behavior of animals, thereby modifying the overall growth pattern. Under these circumstances, it is surprising that neither the precise nature nor the origin of """"""""brain insulin"""""""" or an insulin-like peptide (ILP) has been established. Preliminary data from this laboratory, taken together with other published reports, indicates that brain insulin/ILP is synthesized locally within neurons but may differ, in some fundamental way, from the pancreatic hormone. Moreover, these same preliminary data also suggest that brain insulin/ILP synthesis is subject to regulation by exogenous insulin; an observation which would offer significant insight into the control of insulin activity in the CNS. To more fully address this and several equally basic issues, we propose to: 1) Determine the sites and pattern of insulin/ILP synthesis in the developing rabbit brain by in situ hybridization, 2) Characterize the abundance and size of ILP mRNA at different stages of fetal and immediate postnatal rabbit development by Northern analysis, 3) Determine the effect of exogenous insulin on steady state brain/neuronal ILP mRNA abundance by Northern analysis, 4) Establish the degree of homology between neuronal ILP and authentic pancreatic insulin, and 5) Isolate and characterize the neuronal ILP and gene by screening a brain cDNA library and employing DNA sequencing methods. The studies will be instrumental in establishing the function of ILP and its sequence elements in tissue specific expression and neuronal differentiation.
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