Aging is characterized by defective homeostasis. Based on substantial preliminary studies, the applicant hypothesizes that this altered homeostasis is due in part to impaired transduction of extracellular changes to intracellular effector signals, resulting in blunted cellular responses. This proposal requests support for a detailed examination of this hypothesis, using as a model one major example of an age-associated stimulus-response impairment, namely glucose regulated insulin synthesis in the pancreatic beta cell. The applicant will focus on the immediate glucose effect of stimulation of preproinsulin mRNA translocation, rather than the delayed glucose effect of enhancing preproinsulin mRNA transciption and stablility, both because it is likely to be more relevant to normal glucose homestasis, and because it can be quantitated more precisely. Specifically, he plans to examine whether the impairment in the immediate glucose effect on insulin synthesis in old islets (as assayed by immunoprecipitation of labeled preinsulin after a 30 minute pulse- label period) is (1) consistent with the substrate wite model of regulation of insulin synthesis (2) due to decreased potentiation by the cAMP system (3) affected by the protein kinase C system (4) secondary to changes in intra-islet preproinsulin mRNA levels, or (5) due to decreased tranlational efficiency of preproinsulin mRNA in old islets, and, if so, what steps are impaired. As a natural extension of this work, he will try to delineate the sequences in preproinsulin mRNA that are recognized by putative (protein) factors activated by a glucose stimulus to increase preproinsulin mRNA translation. This proposed project is an open area of investigation, with many possible ramifications, that should allow the applicant to pursue significant, productive, independent investigation of a critical hormone response defect that occurs with aging.
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