CYCLIC GMP AND KB-DEPENDENT TRANSCRIPTION IN NEURONS

描述：环状GMP(CGMP)一直被描述为一种关键的， 外周组织中的多能第二信使。它的影响是 对兴奋性细胞的调节特别重要，如 心肌和平滑肌分泌细胞。循环GMP也经历了 大脑对兴奋性反应的剧烈波动 神经传递。最近的研究才刚刚开始描绘急性 这些cGMP升高对中枢神经系统活动的作用；然而， CGMP对细胞表型的长期影响在很大程度上 未被开发的。初步数据表明，cGMP可以调节细胞周期。 结合kB增强子序列的转录因子的活性。是这样的 Kb结合因子参与了对A基因表达的控制 多种基因，包括细胞附着因子、细胞因子和 抗氧化酶。此外，几种细胞因子，以及细胞 氧化，可以激活kB结合的转录因子。潜力 细胞因子在炎症性脑损伤中的作用 氧化侮辱在无数的大脑疾病中--已经造成了许多 对大脑中kB结合因子的调节感兴趣。 建议的研究将检验cGMP可以调节kB-1的假设。 神经细胞中结合因子的活性。此外，这些研究 将解决cGMP在诱导中发挥作用的可能性 受几种刺激影响的kB依赖转录，包括 谷氨酸和细胞氧化。具体地说，将尝试 目的：(1)鉴定cGMP诱导的kB结合蛋白 增强剂，(2)描绘cGMP-2之间的机制关系 依赖蛋白激酶和kB结合因子的活性，以及(3) 确定cGMP诱导的kB结合激活的单个基因 神经细胞中的因子。

DESCRIPTION: Cyclic GMP (cGMP) has been characterized as a critical, pluripotent second messenger in peripheral tissues. Its effects are particularly important to the regulation of excitable cells such as cardiac and smooth muscle secretory cells. Cyclic GMP also undergoes dramatic fluctuations in the brain in response to excitatory neurotransmission. Recent work has only begun to delineate acute actions of these cGMP elevations on CNS neuronal activity; however, the longterm effects of cGMP on cellular phenotype have been largely unexplored. Preliminary data indicate that cGMP can regulate the activity of transcription factors which bind kB enhancer sequences. Such kB-binding factors have been implicated in control of expression of a diverse array of genes including cell attachment factors, cytokines, and antioxidant enzymes. In addition, several cytokines, as well as cellular oxidation, can activate kB-binding transcription factors. The potential involvement of cytokines in inflammatory brain damage -- and of oxidative insults in a myriad of brain disorders -- has created much interest in the regulation of kB-binding factors in the brain. The studies proposed will test the hypothesis that cGMP can modulate kB- binding factor activity in neuronal cells. Furthermore, these studies will address the possibility that cGMP plays a role in the inductions of kB-dependent transcription effected by several stimuli, including glutamate and cellular oxidation. Specifically, attempts will be made to (1) identify the protein which is induced by cGMP to bind kB enhancers, (2) delineate the mechanistic relationship between cGMP- dependent protein kinase and activity of kB-binding factors, and (3) determine the individual genes activated by cGMP-inducible kB-binding factors in neuronal cells.