M. Cecilia Aguila IBN-9805774 The overall goal of this application is to define the molecular and intracellular mechanisms by which cyclic guanosine 3'5' monophosphate (cGMP) increases somatostatin (SRIF) gene transcription. SRIF is a substance originally found in the brain by its ability to inhibit growth hormone secretion. The production of SRIF is regulated by several intracellular compounds such as nitric oxide, cyclic adenosine monophosphate, and cGMP. In earlier studies, Dr. Aguila found that nitric oxide modulated SRIF gene expression through a cGMP mediated-mechanism. The presence of that intracellular mechanisms in the brain imply that cGMP-mediated control of SRIF synthesis can occur in neurons, raising the intriguing possibility of an unsuspected role for cGMP in the regulation of SRIF gene transcription. This application proposes a combination of physiological, cellular and molecular approaches to address this issue and to test the validity of the intracellular signaling pathways hypothesized to control SRIF production. These experiments will be conducted in primary cultures of neuronal origin and cell lines of either neuronal or glial origin found to produce SRIF. Accordingly, we will examine the hypothesis that a mechanism by which cyclic GMP increases SRIF synthesis involves transcriptional activation of the SRIF gene. Neuronal plasticity depends on the capacity of cells to adjust to environmental stimuli. The reasons for this cell specificity are only now beginning to be understood. The SRIF gene, provides a good model for examining how stimuli detected on the cell surface, influence neuronal gene expression. Advances in the understanding of SRIF biosynthesis may have an impact on areas outside the field of endocrinology by providing new notions of eukaryotic gene regulation.
