MOLECULAR BIOLOGY OF NOREPINEPHRINE BIOSYNTHESIS

神经递质系统对多种长效应激的机械反应 术语操纵，例如在压力或疾病中，是 神经生物学。神经递质生物合成的可塑性要大得多 错综复杂的监管比之前想象的要复杂。这项提议将 研究生物合成调控的分子方面 去甲肾上腺素，一种在一种令人惊讶的 在CNS和外围设备中有大量的函数。 酪氨酸羟基酶(TH)和多巴胺β-羟基酶(DBH)是 参与去甲肾上腺素生物合成的酶在反应中受到调节 对长期的生理、药理和环境刺激。一个 对它们的调控表达的分子描述将是无价的 作为神经递质调节的一般模型以及在 儿茶酚胺能调节机制的具体阐明 神经系统。 该项目将： I.描述膜结合形式和可溶性形式之间的区别 胸径。确定胸径的膜附着方式和 翻译后加工的本质--从膜结合到膜结合 可溶解的形式。 体内胸径和胸腺激素表达的调节 合成去甲肾上腺素的组织，特别是在肾上腺 延髓和中枢神经系统的蓝斑(LC)。 三、PC12细胞中胸腺激素和胸腺激素表达的调控 和原代嗜铬细胞。研究mRNA水平和蛋白水平的调节。 生长因子环磷酸腺苷对胸腺激素基因转录的影响 类似物和糖皮质激素以及这些治疗的组合。 确定大鼠胸径基因的上游调控元件。我假设 CAMP、糖皮质激素和生长有调节因素 各种因素。将确定组织特异性表达的要素。 这项研究的结果将提供一个详细的机制 对去甲肾上腺素生物合成长期调控的解释， 这将对媒体的反应能力产生重要影响。 神经系统对长期的压力和疾病，如高血压， 精神分裂症、抑郁症和阿尔茨海默氏症类型的痴呆。

The mechanistic response of neurotransmitter systems to a variety of long term manipulations, for example in stress or illness, is a central issue in neurobiology. The plasticity of neurotransmitter biosynthesis is much more intricately regulated than previously appreciated. This proposal will study molecular aspects of the regulation of biosynthesis of norepinephrine, a transmitter that plays a crucial role in a surprisingly large number of functions in the CNS and periphery. Tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), two of the enzymes involved in norepinephrine biosynthesis, are regulated in response to long term physiological, pharmacological and environmental stimuli. A molecular description of their regulated expression will be invaluable both as a model for neurotransmitter regulation in general as well as in the specific elucidation of the mechanisms which regulate the catecholaminergic neuronal system. This project will: I. Delineate the differences between membrane-bound and soluble forms of DBH. Determine what is the mode of membrane attachment of DBH and the nature of the post-translational processing from the membrane-bound to the soluble form. II. Determine the regulation of expression of DBH and TH in vivo in tissues which synthesize norepinephrine, specifically in the adrenal medulla and in the locus coeruleus (LC) of the central nervous system. III. Delineate the regulation of expression of DBH and TH in PC12 cells and primary chromaffin cells. Study the regulation of mRNA levels and transcription of the DBH gene in response to growth factors, cyclic AMP analogs and glucocorticoids and combinations of these treatments. IV. Define upstream regulatory elements in the rat DBH gene. I postulate that there are regulatory elements for cAMP, glucocorticoids and growth factors. Elements for tissue specific expression will be determined. The results of this study will provide a detailed mechanistic interpretation of the long term regulation of norepinephrine biosynthesis, which will have important implications for the responsiveness of the nervous system to prolonged stress and disease, such as hypertension, schizophrenia, depression and dementia of the Alzheimer's type.