Regulation of the phenylethanolamine N-methyltransferase gene by hypoxia

氧是哺乳动物细胞正常细胞功能和体内平衡的关键组成部分。哺乳动物能够对氧气减少产生应激反应，以促进缺氧或适应缺氧。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，导致应激激素、皮质酮/皮质醇和肾上腺素的释放。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。虽然肾上腺素合成可能通过 HPA 和 SA 轴调节以应对缺氧应激，但最近的研究表明，肾上腺嗜铬细胞对氧敏感，因此可能调节稳态机制，包括儿茶酚胺生物合成，独立于激素和神经激活。这在嗜铬细胞交感神经支配之前的胎儿发育过程中至关重要。该提案的目标是通过其生物合成酶苯乙醇胺 N-甲基转移酶 (PNMT) 确定缺氧对应激激素肾上腺素的合成和调节的影响。该提案将利用细胞到系统生物学方法来检查缺氧在 PNMT 基因调节中的作用。利用先进的体外细胞和分子技术，将描述调节 PNMT 基因响应缺氧的机制。此外，还将检查氧气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用于检查体外确定的分子调节机制是否参与整个生物体对缺氧应激的反应。这笔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，它还将深入了解应激激素肾上腺素在哺乳动物应激反应和缺氧适应中的作用。

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.