Melatonin: functions and mechanisms of action in placental trophoblast

褪黑激素：胎盘滋养层的功能和作用机制

• 批准号: RGPIN-2019-06778
• 负责人: Vaillancourt, Cathy
• 金额: $ 4.74万
• 依托单位: Institut national de la recherche scientifique
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739102
• 关键词: Melatonin; functions; mechanisms; action; placental

Over the past 14 years, our research program funded by NSERC-discovery grant has allowed demonstrating a crucial role of melatonin in placental function. Our and others research have shown that melatonin has unsuspected beneficial actions on the peripheral reproductive organs, one of which very likely relates to its ability to obviate oxidative stress and placental dysfunction. This research proposal, which is a direct extension of our ongoing NSERC-supported program, aim to understand the role of melatonin and its receptors at the maternal-fetal interface, the placenta, and to develop a cellular model to study the regulation and protective function of this indolamine. The short-term goals of the next 5 years are to elucidate the mechanisms by which melatonin directly and via the activation of its receptors protects the normal placental cells against hypoxia/reoxygenation-induced damage and has cytotoxic effects on placental tumor cells. Specifically, in primary placental villous trophoblast cells, we will dissect the mechanism underlying melatonin protective action on hypoxia/reoxygenation-induced apoptosis and oxidative stress; and determine how melatonin regulates autophagy, endoplasmic reticulum-stress and mitochondrial function. We hypothesize that the differential effects of melatonin in normal trophoblast cells (cytoprotective) and in tumor trophoblast cells (cytotoxic) is mediated, in part, throughout the activation of MT1 and MT2 receptors. Specific Objectives: Specifically, in trophoblast cells, we will dissect the mechanism by which melatonin and its receptors regulate (1) mitochondrial (intrinsic) apoptosis and oxidative stress; (2) autophagy and mitophagy; and (3) endoplasmic reticulum (ER)-stress and mitochondrial function. These research objectives will be addressed using primary cultures of villous trophoblasts from term human placenta, and BeWo human placental choriocarcinoma cell line cultured under normoxia (8% O2) or subject to hypoxia/reoxygenation (4 h hypoxia (0.5% O2) following by 18 h reoxygenation (8% O2)) to induce homoeostasis disruption. Relevance: Our program of research, using trophoblast cells, uses novel approaches to discover the mechanisms by which melatonin plays a cytoprotective (pro-survival) or cytotoxic (pro-death) role. Collectively, the proposed research program will advance our fundamental knowledge of the role of melatonin and its receptors in placenta as well as in normal and abnormal cellular processes (e.g. sleep, cancer, neurodevelopment and reproductive function) and open the way for the development of new preventive and therapeutic molecules in these areas. Melatonin has been suggested for the potential prevention and treatment of a variety of disorders, including obstetric complications, depression, cancer, and neurodegenerative disease.

在过去的14年里，我们的研究计划由NSERC发现资助，已经证明了褪黑激素在胎盘功能中的关键作用。我们和其他人的研究表明，褪黑激素对外周生殖器官有意想不到的有益作用，其中之一很可能与其抑制氧化应激和胎盘功能障碍的能力有关。这项研究计划是我们正在进行的NSERC支持计划的直接延伸，旨在了解褪黑激素及其受体在母胎界面胎盘中的作用，并开发一种细胞模型来研究这种吲哚胺的调节和保护功能。未来5年的短期目标是阐明褪黑激素直接或通过激活其受体保护正常胎盘细胞免受缺氧/复氧诱导的损伤以及对胎盘肿瘤细胞具有细胞毒性作用的机制。具体而言，在原代胎盘绒毛滋养层细胞，我们将解剖的机制褪黑激素的保护作用缺氧/复氧诱导的细胞凋亡和氧化应激，并确定褪黑激素如何调节自噬，内质网应激和线粒体功能。我们推测，褪黑激素在正常滋养层细胞（细胞保护）和肿瘤滋养层细胞（细胞毒性）的差异效应是介导的，部分，在整个激活MT 1和MT 2受体。具体目标：具体来说，在滋养层细胞中，我们将剖析褪黑激素及其受体调节（1）线粒体（内在）细胞凋亡和氧化应激的机制;（2）自噬和线粒体自噬;和（3）内质网（ER）-应激和线粒体功能。这些研究目的将使用来自足月人胎盘的绒毛滋养层细胞的原代培养物和BeWo人胎盘绒毛膜癌细胞系在常氧（8% O2）或缺氧/复氧（4 h缺氧（0.5% O2），随后18 h复氧（8% O2））下培养以诱导体内平衡破坏来解决。相关性：我们的研究计划，使用滋养层细胞，使用新的方法来发现褪黑激素发挥细胞保护（促生存）或细胞毒性（促死亡）作用的机制。总的来说，拟议的研究计划将推进我们对褪黑激素及其受体在胎盘以及正常和异常细胞过程（例如睡眠，癌症，神经发育和生殖功能）中作用的基本知识，并为这些领域开发新的预防和治疗分子开辟道路。褪黑激素已被建议用于潜在的预防和治疗各种疾病，包括产科并发症，抑郁症，癌症和神经退行性疾病。