低氧下大鼠下丘脑CRF合成与分泌的第二信使调控

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	低氧下大鼠下丘脑CRF合成与分泌的第二信使调控
	邝霞
学位类型	硕士
导师	杜继曾
	1995
学位授予单位	中国科学院西北高原生物研究所
学位授予地点	中国科学院西北高原生物研究所
学位专业	生理生化专业
关键词	下丘脑促肾上腺皮质激素释放因子(Crf) 合成与分泌第二信使通路低氧十鼠动物生理学
摘要	本研究利用模拟高原低氧的方法，探讨了低氧下大鼠下丘脑CRF合成和分泌所特有的时程变化规律，并结合第三脑室注射第二信使通路（cAMP-AC通路和PKC通路）激动剂和抑制剂，初步研究了低氧下CRF合成和分泌及其调控中的第二信使通路参与机制。将大鼠置于人为模拟的低氧环境中，海拔高度分别为5000m和7000m，以本地海拔2300m作为对照。低氧时间分别为1小时、1天、5天、10天和25天。结果显示：正中隆起CRF的含量在急性低氧1小时和1天两组中表现出明显下降；亚急性低氧5天，正中隆起CRF含量与对照组无显著差异；慢性低氧10天和25天两组正中隆起CRF含量均无明显变化。而表现在下丘脑CRF含量方面，急性低氧1小时变化不明显, 而在急性低氧1天时才表现出显著的下降；亚急性5天，下丘脑CRF含量表现出升高趋势；10天和25天慢性低氧组中则与对照基本一致。因为正中隆起处CRF的含量是反应分泌活动的指标，而下丘脑及CRF含量则代表CRF合成与分泌的净效应，故我们基于现有实验结果可以得出如下结论：急性低氧应激中大鼠CRF的分泌活动显著增加，但其时程较短尚未能引起CRF合成的迅速增加；在亚急性低氧时段，由于CRF合成逐渐增加。其合成速率与分泌速率的相对变化导致下丘脑及正中隆起CRF含量的变化；而在较长时间的慢性低氧应激中，CRF的合成与分泌几乎等同于对照的水平，反应出动物对这种慢性的长时间低氧过程中已表现出一定程度的耐受性，下丘脑cAMP含量仅在急性低氧1小时有显著的升高，在其他较长时间的低氧中均无明显变化。大鼠第三脑室注射AC激动剂Forskolin和PKC激动剂TPA，急性低氧1小时，Forskolin和TPA均能刺激CRF的分泌增强，而PKA抑制剂和PKC抑制剂H_7则能够显著降低由低氧引起的CRF分泌增加。Forskolin对大鼠下丘脑cAMP含量升高显著的刺激作用。表明急性低氧（1小时）应激中cAMP-AC 通路和PKC通路均作为第二信使通路参与介导CRF的分泌。大鼠脑室注射不同剂量的Forskolin和TPA，急性低氧1小时，在一定剂量范围内，均表现出随注射剂量增加CRF分泌也增加。提示在一定范围内，随cAMP-AC通路和PKC通路活性的增强，CRF分泌也增加。综上所述，可结论如下：低氧下大鼠CRF的合成和分泌有其特有的时程变化规律；大鼠急性低氧应激下cAMP－AC通路和PKC通路都被激活并作为第二信使通路参与CRF分泌的调节，而且在一定程度上CRF分泌增加的幅度随这两条通路被激活的程度增加而增大；在急性低氧应激中cAMP作为第二信使介导CRF的分泌增加，而在较长时间的低氧中还未见可测的效应，故推测在更长时间的低氧应激中，CRF合成与分泌的是可能有另外的第二信使通路参与介导或还存在其它的调节机制。
其他摘要	Using the methods of simulating hypoxia and i.c.v. injection of the second messenger pathways activators and inhibitors, we have studied the time course of hypothalamic CRF synthesis and secretion in hypoxia of rats, and the second messenger pathways involved its regulation. Hypoxia experiments were accomplished by simulating altitude of 5000m and 7000m respectively, for 1 hour、1 day、5 days、10 days and 25 days, using 2300 m as control. It showed that, the content of CRF in median eminence reduced significantly during acute hypoxia for a hour and 1 day, but there was no considerably change during prolonged hypoxia exposure for 5 days、10 days and 25 days. However, the content of CRF in hypothalamus did not change in acute hypoxia for 1 hour, but decreased obviously in 1 day, and increased in hypoxia for 5 days to some degree, but had no changes during chronic hypoxia for 10 days and 25 days. Median eminence CRF content reflects the secretion of CRF, and hypothalamic CRF content represent the net effect of CRF synthesis and secretion. So we can concluded that, in acute hypoxia, the CRF secretion increases markedly, but the short time-course cannot induce its synthesis. During the 5 days hypoxia phase, with the increase of CRF synthesis, the relative change of synthesis and secretion results in the changes of hypothalamic and median eminence CRF contents. However, during long term of chronic hypoxia, both CRF synthesis and secretion return to normal level, it seemed that animals have developed intolerance to the stress to some extent during prolonged chronic hypoxia exposure. The cAMP contents in hypothalamus only increased markedly in acute hypoxia for 1 hour. In acute hypoxia for 1 hour, both forskolin and TPA i.c.v. injection stimulated CRF secretion significantly, respectively. Either PKA inhibitor or H_7 i.c.v. injection inhibited CRF secretion induced by acute hypoxia exposure. Only forskolin had notably effect on hypothalamic cAMP increase. It suggested that both cAMP-AC pathway and PKC pathway are involved in CRF secretion as second messenger pathways during acute hypoxia (for 1 hour). And with the forskolin and TPA dosage increasing, the CRF secretion also increase. It indicated that, to some extent, with the cAMP-AC and PKC pathway being activated, CRF secretion also be stimulated during acute hypoxia. In conclusion, CRF synthesis and secretion has showed markedly time-course change during hypoxia in rats. In acute hypoxia, both cAMP-AC pathway and PKC pathway are activated, and involved in regulation of CRF secretion as second messenger pathways, Moreover, to some extent, with cAMP-AC and PKC pathways activity increasing, CRF secretion also be stimulated. cAMP plays an important role in CRF secretion as second messenger during acute hypoxia, but has no consequential effects as prolonged hypoxia exposure. So we proposed that, during long term of chronic hypoxia, there may be some other mechanisms be involved in regulation of CRF synthesis and secretion.
页数	44
语种	中文
文献类型	学位论文
条目标识符	http://210.75.249.4/handle/363003/3338
专题	中国科学院西北高原生物研究所
推荐引用方式 GB/T 7714	邝霞. 低氧下大鼠下丘脑CRF合成与分泌的第二信使调控[D]. 中国科学院西北高原生物研究所. 中国科学院西北高原生物研究所,1995.

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