MOLECULAR BIOLOGY OF NOREPINEPHRINE BIOSYNTHESIS

神经递质系统对各种长时间的 长期操纵，例如在压力或疾病中，是一个中心问题， 神经生物学 神经递质生物合成的可塑性 比以前认识到的更复杂。 这项建议会 研究生物合成调节的分子方面， 去甲肾上腺素，一种在一种令人惊讶的 中枢神经系统和外周神经系统中的大量功能。 酪氨酸羟化酶（TH）和多巴胺β-羟化酶（DBH），两种 参与去甲肾上腺素生物合成的酶， 长期的生理、药理和环境刺激。 一 对它们调节表达的分子描述将是非常宝贵的， 作为神经递质调节的模型， 具体阐明了调节儿茶酚胺能神经递质的机制， 神经系统 该项目将： I. 描述膜结合型和可溶性型之间的差异， DBH。 确定DBH的膜附着模式和 从膜结合到膜结合的翻译后加工的性质 可溶形式 二. 确定在体内DBH和TH表达的调节， 合成去甲肾上腺素的组织，特别是肾上腺 髓质和中枢神经系统的蓝斑（LC）中。 三. 阐明PC 12细胞中DBH和TH表达的调控 和初级嗜铬细胞。 研究mRNA水平的调节， DBH基因的转录响应生长因子，环磷酸腺苷 类似物和糖皮质激素以及这些治疗的组合。 四. 定义大鼠DBH基因的上游调控元件。 我假设 cAMP、糖皮质激素和生长的调节元件 因素 将确定用于组织特异性表达的元件。 这项研究的结果将提供一个详细的机制， 去甲肾上腺素生物合成的长期调节的解释， 这将对联合国的反应能力产生重要影响。 神经系统长期压力和疾病，如高血压， 精神分裂症、抑郁症和阿尔茨海默型痴呆症。

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.