Regulation of the phenylethanolamine N-methyltransferase gene by hypoxia

氧是哺乳动物细胞中正常细胞功能和稳态的关键组分。哺乳动物能够引起对减少的氧气的应激反应，以促进去除或适应缺氧。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）轴介导的，导致释放应激激素，皮质酮/皮质醇和肾上腺素。肾上腺素由肾上腺合成和释放，是负责哺乳动物“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以通过HPA和SA轴调节，以响应缺氧应激，最近的研究表明，肾上腺嗜铬细胞是氧敏感的，因此可以调节稳态机制，包括儿茶酚胺的生物合成，独立于激素和神经激活。这在胎儿发育过程中，在嗜铬细胞的交感神经支配之前是至关重要的。本提案的目的是确定缺氧对应激激素肾上腺素的合成和调节的影响，通过其生物合成酶苯乙醇胺N-甲基转移酶（PNMT）。本研究将利用细胞到系统生物学的方法来研究缺氧在PNMT基因调控中的作用。利用先进的体外细胞和分子技术，参与调节的PNMT基因在缺氧的机制将划定。此外，还将研究氧在调节肾上腺素合成的应激轴激活中的作用。此外，急性和慢性缺氧的体内研究也将被用来检查是否在体外确定的分子调控机制参与整个生物体的缺氧应激反应。这项资助的结果将为缺氧反应所涉及的基本细胞过程提供新的见解。此外，它还将提供洞察应激激素，肾上腺素，在哺乳动物应激反应和适应缺氧的作用。

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.