Regulation of the phenylethanolamine N-methyltransferase gene by hypoxia

氧是哺乳动物细胞正常功能和动态平衡的关键成分。哺乳动物能够对低氧产生应激反应，以利于清除或适应低氧。哺乳动物的应激反应是通过激活下丘脑-垂体-肾上腺(HPA)轴和交感-肾上腺(SA)轴，导致应激激素、皮质酮/皮质醇和肾上腺素的释放而介导的。肾上腺素是由肾上腺合成和释放的，是哺乳动物“战斗或逃跑反应”的神经递质/神经激素。虽然肾上腺素的合成可能是通过HPA和SA轴来调节的，但最近的研究表明，肾上腺嗜铬细胞是氧敏感的，因此可能调节包括儿茶酚胺生物合成在内的动态平衡机制，而不依赖于激素和神经的激活。在嗜铬细胞交感神经支配之前的胎儿发育过程中，这是至关重要的。本研究的目的是通过生物合成酶苯乙醇胺N-甲基转移酶(PNMT)来确定低氧对应激激素肾上腺素合成和调节的影响。这项建议将利用细胞到系统生物学的方法来研究低氧在PNMT基因调控中的作用。利用先进的体外细胞和分子技术，将阐明PNMT基因对低氧反应的调控机制。此外，还将研究氧在调节肾上腺素合成的应力轴激活中的作用。此外，还将利用急性和慢性低氧的体内研究来检查体外确定的分子调控机制是否涉及整个有机体对低氧应激的反应。这项资助的结果将为人们对低氧反应所涉及的基本细胞过程提供新的见解。此外，它还将深入了解应激激素肾上腺素在哺乳动物对低氧的应激反应和适应中的作用。

Oxygen is a critical component of normal cellular function and homeostasis in mammalian cells. Mammals are capable of eliciting a stress-response to reduced oxygen to facilitate either removal or adaptation to hypoxia. The mammalian stress-response is mediated via activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympatho-adrenal (SA) axis, resulting in the release of the stress hormones, cortisosterone/cortisol and adrenaline. Adrenaline is synthesized and released by the adrenal glands and is the neurotransmitter/neurohormone responsible for the mamallian "fight or flight response". Although adrenaline synthesis may be regulated via the HPA and SA axis in response to hypoxic stress, recent studies have shown that adrenal chromaffin cells are oxygen sensitive and may therefore regulate homeostatic mechanism, including catecholamine biosynthesis, independent of hormonal and neural activation. This is critically important during fetal development prior to sympathetic innervation of chromaffin cells. The goal of this proposal is to determine the impact hypoxia on the synthesis and regulation of the stress hormone, adrenaline, via its biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT). This proposal will utilize a cell to systems biology approach to examine the role of hypoxia in the regulation of the PNMT gene. Utilizing advanced in vitro cellular and molecular techniques, the mechanism involved in the regulation of the PNMT gene in response to hypoxia will be delineated. In addition, the role of oxygen in modulating the stress axis activation of adrenaline synthesis will also be examined. Furthermore, in-vivo studies of acute and chronic hypoxia will also be utilized to examine the whether the molecular regulatory mechanisms identified in-vitro are involved in the whole organism's response to hypoxic stress. The results from this grant will provide new insight into the fundamental cellular processes involved in response to hypoxia. In addition, it will also provide insight into the role of stress the hormone, adrenaline, in the mammalian stress response to and in the adaptation to hypoxia.