TRANSCRIPTIONAL CONTROL IN NEUROHYPOPHYSIAL NEURONS

描述：过去对研究资源的重大投资 25年来，已经卓有成效地证明了CNS肽在 生理调节、行为和病理状态。尽管 它们在健康和疾病方面的重要性， 已经致力于建立分子机制， 调节神经肽的合成。由于这些信息对于 了解它们参与生物学功能， 这项建议的目的是进一步了解分子 控制神经肽基因转录的机制。 该项目将重点关注四种神经肽的调节： 下丘脑中的加压素催产素、胆囊收缩素和甘丙肽， CNS的神经垂体系统（NHS）。NHS是一个理想的实验性 用于确定转录调控的模型系统 上述基因它在神经内分泌和 行为功能（抗利尿，血压控制，压力， 分娩，哺乳和母性行为），这些神经元表现出 对刺激的强烈反应。使用实验室老鼠， 研究表明，身体水分平衡的变化， 饮用盐水溶液或注射高渗盐水， NHS神经元释放所有四种神经肽，并改变它们的“速率”。 肽合成，表现为信使RNA水平的增加。 在这个项目中，重点将放在碱性亮氨酸拉链家族， 转录因子（bZips，包括因子Fos、Jun和CREB）。 基于bZip转录因子在细胞凋亡中发挥作用的假设， 调节NHS神经肽的转录，这项研究将：1） 通过血管加压素、催产素、甘丙肽和 胆囊收缩素基因，2）通过迁移率改变DNA结合试验显示， 在这些基因的启动子区域中存在特异的DNA序列， 与bZip转录因子相互作用的神经肽基因，和3） 用体外转染的启动子序列证明， 神经细胞，这些序列是至关重要的控制 神经肽基因转录什么是发现使用NHS作为一个 模型系统将与这些重要的基因调控相关， 肽在神经内分泌功能以及其他神经系统中的作用 中枢神经系统，其中广泛的神经，内分泌和 免疫功能归因于这些神经活性物质。

DESCRIPTION: A significant investment of research resources over the past 25 years has fruitfully demonstrated the role of CNS peptides in physiological regulation, behavior, and pathological states. In spite of their recognized importance in health and disease, comparatively little work has been devoted to establishing the molecular mechanisms that regulate neuropeptide synthesis. Since this information is crucial for understanding their participation in biological functions, the long-term objective of this proposal is to further our knowledge of the molecular mechanisms that control the transcription of neuropeptide genes. This project will focus upon the regulation of four neuropeptides: vasopressin oxytocin, cholecystokinin, and galanin, in the hypothalamo- neurohypophysial system (NHS) of the CNS. The NHS is an ideal experimental model system for determining the transcriptional regulation of the aforementioned genes. It is of great importance in neuroendocrine and behavior function (anti-diuresis, blood pressure control, stress, parturition, lactation, and maternal behaviors), and these neurons exhibit a very dramatic response to stimulation. Using the laboratory rat, investigations show that changes in body water balance, by maintenance on drinking solutions of salt water or injection of hypertonic saline, causes NHS neurons to release all four neuropeptides and alter their 'rate' of peptide synthesis, manifested by increases in messenger RNA levels. In this project, the focus will be upon the basic leucine zipper family of transcription factors (bZips, including the factors Fos, Jun an CREB). Based upon the hypothesis that bZip transcription factors play a role in regulating the transcription of NHS neuropeptides, this research will: 1) demonstrate by in situ hybridization of vasopressin, oxytocin, galanin and cholecystokinin genes, 2) show by mobility shift DNA-binding assays that there are specific DNA sequence in the promoter regions of these neuropeptide genes that interact with bZip transcription factors, and 3) demonstrate with in vitro transfection of promoter sequences in cultured neural cells, that these sequences are crucial for the control of neuropeptide gene transcription. What is discovered using the NHS as a model system will have relevance to gene regulation of these important peptides in neuroendocrine function as well as in other neural systems of the CNS, where a wide range of neurological, endocrinological and immunological functions are attributed to these neuroactive substances.