Regulation of the phenylethanolamine N-methyltransferase gene by hypoxia

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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.