Molecular Biology of Norepinephrine Biosynthesis

描述(申请人提供)：去甲肾上腺素(NE)是一种重要的儿茶酚胺神经递质/激素，调节广泛的生理反应。NE神经传递的改变与几种流行的疾病有关，包括心血管疾病，如高血压/低血压，神经精神疾病，如抑郁症和帕金森病。调节NE生物合成酶酪氨酸羟基酶(TH)和多巴胺β-羟基酶(DBH)的表达是调节NE系统的关键机制。这项建议的具体目的是：1.)测定不同时间或重复束缚应激大鼠蓝斑TH和DBH转录激活的动力学和持续性。2.)研究在不同持续时间或重复应激条件下，蓝斑和肾上腺髓质中TH和DBH基因转录激活途径的动态变化。3.)确定单一和重复的束缚应激对大鼠肾上腺髓质和蓝斑中瞬时或长期转录因子从头合成的诱导与TH和DBH基因表达的调节有关。4.)开始研究以上观察到的胁迫反应因子串扰调节TH和DBH基因表达的机制。具体研究AP-L因子和EGR1在TH转录调控中的相互作用。这些结果将为理解在急性和重复暴露于应激情况下中枢和外周儿茶酚胺产生系统基因表达激活的不同转录机制提供关键的理解。这些发现将有助于开发新的策略，以防止儿茶酚胺神经传递中有害的适应不良变化，同时加强其有益的适应方面。

DESCRIPTION (provided by applicant): Norepinephrine (NE) is a crucial catecholamine neurotransmitter/hormone mediating a wide range of physiological responses. Alterations in NE neurotransmission are associated with several prevalent disorders, including cardiovascular disorders such as hypertension/hypotension, neuropsychiatric disorders, such as depression and in Parkinson's disease. Regulation of the expression of NE-biosynthetic enzymes, tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), is a key mechanism of regulation of the NE systems. The specific aims of this proposal are: 1.) Determine the kinetics and the persistence of activation of TH and DBH transcription in rat locus coeruleus with different duration or repetitions of immobilization stress. 2.) Examine the dynamics of pathways involved in transcriptional activation of TH and DBH gene expression in locus coeruleus and adrenal medulla with different durations or repetitions of stress. 3.) Identify the induction of de novo synthesis of transient or long-lasting transcription factors in rat adrenal medulla and locus coeruleus associated with regulation of TH and DBH gene expression by exposure to single and repeated immobilization stress. 4.) Begin to characterize the mechanisms by which the above observed stress responsive factors cross-talk to regulate TH and DBH gene expression. Specifically examine the interaction of AP-l factors and Egr1 on the regulation of TH transcription. The results will provide a crucial understanding of the different transcriptional mechanisms of activation of gene expression of catecholamine producing systems in the CNS and the periphery with acute and repeated exposure to stressful situations. These findings will contribute to the development of new strategies to prevent the harmful maladaptive changes in catecholamine neurotransmission, while enhancing its beneficial adaptive aspects