The overall objective is to study the mechanisms underlying the activation and regulation of key metabolic processes in the neonate, viz hepatic gluconeogenesis, glycogenolysis and fat metabolism. This activation, in part, involves events mediated at the cell surface by hormones linked to the adenylate cyclase system. Modulation of this enzyme by hormones involves interactions among three plasma membrane proteins: viz, the receptor, a guanine necleotide-sensitive component (dubbed G- or N- protein), and C, the catalytic component of the cyclase. In addition, there are at least two specific effectors, the hormone and GTP. The project is a systematic study of the ontogeny and functional integration of the three components of hepatic adenylate cyclase system during neonatal development, and the relationship of these changes to overall control of hepatic glucose output in the neonate. The long-term goals include studies to understand the long-term regulation of the adenylate cyclase system and the regulation of the developmental expression of key components of the system.
The specific aims for this project period are i) to study the potential role of inhibitory components in this system in the hormonal responsiveness of the neonatal hepatocyte so as to understand whether the subsensitivity of the neonatal hepatocyte to hormonal stimulation may be a result of endogenous inhibition of the cyclase system; ii) to measure the concentrations of the stimulatory and inhibitory components and to decipher the molecular basis for the refractoriness of adenylate cyclase during early neonatal development; iii) to study whether uncoupling of, for example, the Beta-receptor, from the regulatory unit results from or is causally related to possible phosphorylation of the receptor and/or alterations in the subunits of N. These studies should be valuable in understanding molecular mechanisms underlying neonatal hypoglycemia and the problem of tissue refractoriness to hormones which is a frequently encountered phenomenon, e.g., in tissues of diabetic persons or in abnormal development.
