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

ROS 在缺氧介导的苯乙醇胺 N-甲基转移酶基因调节中的作用

• 批准号: RGPIN-2018-06833
• 负责人: Tai, TzeChun
• 金额: $ 2.11万
• 依托单位: Laurentian University of Sudbury
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=760902
• 关键词: ROLE; ROS; HYPOXIA; MEDIATED; REGULATION

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.

氧气是哺乳动物细胞正常细胞功能和稳态的重要组成部分，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下丘脑垂体的激活来介导的。 - 肾上腺 (HPA) 轴和交感肾上腺 (SA) 轴，导致应激激素、皮质酮/皮质醇和肾上腺素主要由肾上腺的嗜铬细胞合成和释放，是负责“战斗或逃跑反应”的神经递质/神经激素，尽管肾上腺素的合成可能通过 HPA 和 SA 轴来调节以应对缺氧应激。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，不依赖于激素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。此外，最近报道的研究表明，氧化应激参与了细胞对缺氧的反应。然而，ROS 在涉及肾上腺素合成调节的细胞机制中的作用，特别是 PNMT 基因的表观遗传调节，尚不清楚。该提案将利用细胞到系统生物学的方法来检查。缺氧在 PNMT 基因调节中的作用 利用体外 PC12 细胞培养模型和先进的体外细胞和分子技术，将了解调节 PNMT 基因响应缺氧和 ROS 的细胞和分子机制。此外，还将研究表观遗传调节剂在介导缺氧细胞反应中的作用。此外，还将利用缺氧暴露的体内啮齿动物模型来检查是否已确定分子调节机制。体外参与整个生物体对缺氧应激的反应。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，它还将提供对应激激素的作用的深入了解。肾上腺素在哺乳动物对应激反应和缺氧适应中发挥作用。