The control of glucose homeostasis is critical to human health. Central to this process is the regulation of gluconeogenesis by the liver and kidney cortex. The rate limiting enzyme in glucose synthesis is phosphoenolpyruvate carboxykinase (GTP) (PEPCK; the overexpression of the gene for PEPCK in the liver of mice has, by itself, been shown to induce the symptoms of diabetes. The level of PEPCK in tissues is controlled by the rate of its gene transcription, which is acutely and markedly increased by starvation and by a diet devoid of carbohydrate and is inhibited by a diet high in carbohydrate. The mechanism of regulation of PEPCK gene transcription by hormones and diet is the topic of this grant application. The proposed research will focus on the interaction between cAMP (the signal of the catabolic state), glucocorticoids and other regulatory factors such as Nuclear Factor I, Steroid regulatory Co-activator-1 (SRC-1) and CREB binding protein (CBP). Recent work in Dr. Hanson's laboratory has shown that CREB Binding protein (CBP) can integrate the multiple signals that control PEPCK gene transcription in mammals and may thus hold the key to understanding the interaction between cAMP and glucocorticoids in controlling glucose output from the liver. Dr. Hanson plans to elucidate the manner in which the complex set of signals that control PEPCK gene transcription coordinated, using an in vitro transcription system. Based on the results, he will attempt to establish a physiological model of much greater resolution to explain the complex pattern of hormonal regulation of PEPCK gene transcription in mammals.
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