ROLE OF ROS IN HYPOXIA-MEDIATED REGULATION OF THE PHENYLETHANOLAMINE N-METHYLTRANSFERASE GENE

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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 predominantly by the chromaffin cells of the adrenal glands and is the neurotransmitter/neurohormone responsible for the “fight or flight response”. Although adrenaline synthesis may be regulated via the HPA and SA axis in response to hypoxic stress, 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. Studies to date support a role of reactive oxygen species (ROS) is involved in the cellular responses to hypoxia. Furthermore, recently reported studies suggest that oxidative stress and ROS alters epigenetic gene regulation mechanism. However the role of ROS in cellular mechanisms involved in the regulation of the adrenaline synthesis and in particular epigenetic regulation of the PNMT gene is not known. This proposal will utilize a cell to systems biology approach to examine the role of hypoxia in the regulation of the PNMT gene. Utilizing an in-vitro PC12 cell culture model and advanced in vitro cellular and molecular techniques, the cellular and molecular mechanism involved in the regulation of the PNMT gene in response to hypoxia and ROS will be delineated. In addition, the role of epigenetic regulators in mediating the hypoxic cellular response will also be investigated. Furthermore, in vivo rodent models of hypoxia exposure will 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.