NICOTINE EFFECTS ON THE ADRENAL MEDULLA AND BRAIN

描述(改编自申请人的摘要)： 这是竞争续订的第一次修订，得分为189 (29.8)来自罗切斯特大学的副教授，他一直是 对酪氨酸羟化酶的研究已有多年。他的研究主要是 专注于压力相互作用，但他现在有兴趣研究 尼古丁对该调节酶表达影响的复杂性 儿茶酚胺合成。 尼古丁促进肾上腺儿茶酚胺的释放和生物合成 在延髓和大脑中。对肾上腺髓质的影响可能在 尼古丁的外周作用，例如对心血管系统的作用。然而， 脑对儿茶酚胺能系统的影响可能介导了一些尼古丁 令人上瘾的特性。酪氨酸羟化酶(TH)基因表达增强 每天两次后肾上腺髓质和蓝斑(LC) 注射尼古丁14天；一次注射不会引起TH。 反复注射尼古丁会导致几个信号的重复激活 儿茶酚胺能细胞中的通路。尼古丁拮抗剂不能完全 阻断尼古丁对TH的诱导，提示这种诱导可能包括 跨突触信号通路。此外，TH基因表达的诱导 假设涉及转录和转录后转录 机械装置。研究人员将使用两种动物模型(大鼠和转基因动物 小鼠)和组织培养系统(PC12细胞，大鼠嗜铬细胞瘤)以 1)检测TH基因表达的增强诱导是否观察到 尼古丁反复治疗是通过转录和/或 转录后机制；2)检测肾上腺嗜铬细胞 受体参与TH基因表达的增强诱导， 在反复服用尼古丁后发生；以及3)检验以下假设 在LC中TH的诱导增强是由于反复刺激 细胞内信号通路。由活跃的nAChRs。

DESCRIPTION(Adapted from applicant's abstract): This is the first revision of a competing renewal that received a score of 189 (29.8) from an associate professor at the University of Rochester, who has been studying tyrosine hydroxylase for many years. His research has principally concentrated on stress interactions, but he is now interested in investigating the complexities of nicotine effects on expression of this regulatory enzyme in catecholamine synthesis. Nicotine increases catecholamine release and biosynthesis in the adrenal medulla and in the brain. The effects on the adrenal medulla likely mediate nicotine's peripheral actions, e.g. on the cardiovascular system. However, brain effects on catecholaminergic systems might mediate some of nicotine's addictive properties. Tyrosine hydroxylase (TH) gene expression is enhanced in both the adrenal medulla and the locus coeruleus (LC) after twice daily injections of nicotine for 14 days; a single injection does not induce TH. Repeated nicotine injections result in repeated activation of several signaling pathways in catecholaminergic cells. Nicotinic antagonists do not completely block induction of TH by nicotine, suggesting that the induction may involve transsynaptic signaling pathways. Further, the induction of TH gene expression is hypothesized to involve both transcriptional and post-transcriptional mechanisms. The investigator will use two animal models (rat and transgenic mouse) and a tissue culture system (PC12 cells, a rat pheochromocytoma)to 1)Test whether the enhanced induction of TH gene expression observed after repeated nicotine treatment is mediated by transcriptional and/or post-transcriptional mechanisms; 2) Test which adrenal chromaffin cell receptors participate in the enhanced induction of TH gene expression which occurs after repeated nicotine administration; and 3) Test the hypothesis that the enhanced induction of TH in the LC is due to repeated stimulation of intracellular signaling pathways. by active nAChRs.