POWRE: Transcriptional Regulation of the Somatostatin Gene in Neurons

本申请的总体目标是确定环鸟苷3‘5’一磷酸(CGMP)促进生长抑素(SRIF)基因转录的分子和细胞内机制。SRIF是一种最初在大脑中发现的物质，其作用是抑制生长激素的分泌。SRIF的产生受几种细胞内化合物的调节，如一氧化氮、环磷酸腺苷和cGMP。在早期的研究中，阿吉拉博士发现一氧化氮通过cGMP介导的机制调节SRIF基因的表达。大脑中这种细胞内机制的存在意味着cGMP介导的SRIF合成的控制可以在神经元中发生，这增加了cGMP在SRIF基因转录调控中意外发挥作用的有趣可能性。这项申请提出了一种生理、细胞和分子方法的组合来解决这个问题，并测试假设的细胞内信号通路的有效性，以控制SRIF的产生。这些实验将在神经元来源的原代培养和产生SRIF的神经元或神经胶质来源的细胞系中进行。因此，我们将检验这样一种假设，即循环GMP增加SRIF合成的机制涉及SRIF基因的转录激活。神经元的可塑性取决于细胞对环境刺激的调节能力。这种细胞特异性的原因现在才开始被理解。SRIF基因为研究细胞表面检测到的刺激如何影响神经元基因表达提供了一个很好的模型。了解SRIF生物合成的进展可能会对内分泌学领域以外的领域产生影响，为真核基因调控提供新的概念。

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.