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流行的疾病相关，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。NE生物合成酶酪氨酸羟化酶（TH）和多巴胺β-羟化酶（DBH）的表达的调节是NE系统调节的关键机制。本提案的具体目标是：1）测定不同持续时间或重复次数的束缚应激对大鼠蓝斑TH和DBH转录激活的动力学和持续性。2.）的情况。检测不同持续时间或重复应激下蓝斑和肾上腺髓质TH和DBH基因表达转录激活途径的动态变化。3.）第三章通过暴露于单次和重复固定应激，确定大鼠肾上腺髓质和蓝斑中与TH和DBH基因表达调节相关的瞬时或持久转录因子从头合成的诱导。4.）开始表征上述观察到的胁迫响应因子相互作用以调节TH和DBH基因表达的机制。具体研究AP-1因子与Egr 1相互作用对TH转录的调控。结果将提供一个关键的理解不同的转录机制激活的基因表达的儿茶酚胺生产系统在中枢神经系统和周边急性和反复暴露于压力的情况下。这些发现将有助于发展新的策略，以防止有害的适应不良变化的儿茶酚胺神经传递，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