Molecular Biology of Norepinephrine Biosynthesis

描述（由申请人提供）：去甲肾上腺素（NE）是一种重要的儿茶酚胺神经递质/激素，介导广泛的生理反应。NE神经传递的改变与几种常见疾病有关，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。酪氨酸羟化酶（TH）和多巴胺-羟化酶（DBH）等NE-合成酶的表达调控是调控NE系统的关键机制。本提案的具体目的是：1)测定不同时间或重复固定应激下大鼠蓝斑中TH和DBH转录激活的动力学和持久性。2)。在不同持续时间或重复的应激下，研究蓝斑和肾上腺髓质中TH和DBH基因表达的转录激活途径的动力学。3)。确定暴露于单一和重复固定应激下，大鼠肾上腺髓质和蓝斑中与TH和DBH基因表达调控相关的瞬时或长期转录因子的重新合成诱导。4)。开始描述上述观察到的应激反应因子串扰调控TH和DBH基因表达的机制。具体研究ap - 1因子与Egr1在TH转录调控中的相互作用。该结果将为急性和反复暴露于压力环境下的中枢神经系统和外周神经系统中儿茶酚胺产生系统基因表达激活的不同转录机制提供重要的理解。这些发现将有助于开发新的策略，以防止有害的儿茶酚胺神经传递的不适应变化，同时增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