Cellular and molecular studies of adaptive survival responses induced by mild heat stress at 40°C in mammalian cells

40℃轻度热应激诱导哺乳动物细胞适应性生存反应的细胞和分子研究

• 批准号: RGPIN-2017-05733
• 负责人: AverillBates, Diana
• 金额: $ 5.17万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=710848
• 关键词: Cellular; molecular; studies; adaptive; survival

Stress response pathways allow cells to sense and respond to adverse environmental changes. Sub-lethal doses of different stresses (reactive oxygen species (ROS), heat shock, environmental toxins) can induce adaptive survival responses that allow cells and organisms to continue normal function in the face of an adverse stimulus. Adaptive responses are mediated by a core group of powerful anti-apoptotic genes (heat shock proteins (Hsp), antioxidants) that protect against diverse toxic stresses and enable the cell to survive. An adaptive response could counteract stress-induced damage to lipids, proteins and DNA and/or increase tolerance to such damage. If the adaptive response cannot protect the cell, then the damaged cell would be eliminated by apoptosis and/or necroptosis. We found that an adaptive survival response induced at 40C protected mammalian cells against toxic stresses such as ROS and 43C heat shock. In addition to Hsps, antioxidants and ER stress proteins were upregulated by this adaptive response. However, mechanisms underlying this adaptive response induced at 40C are not entirely understood. Long-term goals: Our ongoing research aims to further clarify the cellular and molecular basis of mild thermotolerance, an adaptive survival response induced in cells exposed to a low, non-lethal temperature of 40C. Thermotolerance protects cells against adverse effects of a variety of environmental stresses and my hypothesis is that preconditioning by low-dose heat stress at 40C induces multiple defense systems that protect cells against adverse effects of more aggressive stresses and environmental toxins. A common response of cells to stresses and toxins is increased production of ROS such as superoxide and H2O2. Our specific short-term objectives are to: 1. Determine whether mild heat shock at 40C increases ROS, which then induce the adaptive survival response. 2. Establish the role of the Nrf2 signaling pathway in the adaptive survival response (40C) and possible links between this pathway and the ER stress- and Hsf1 (heat shock factor 1)-mediated stress responses. 3. Determine if the threshold between induction of cell survival responses (ER stress, autophagy) and cell death (apoptosis) at 42-43ºC is altered in preconditioned cells at 40C. Understanding of mechanisms involved in cellular adaptation to stressful environments will inform the multitude of investigations on exposure of humans and wildlife to toxic pollutants, identify more sensitive biomarkers for toxicological risk assessment and demonstrate how to utilize the healing capacity of the adaptive survival response to protect against and repair stress-induced damage to biological systems. Armed with this knowledge, novel strategies (e.g. boost endogenous survival responses) will be developed to protect living organisms against toxic agents and to slow or halt dysfunction in our aging population.

应激反应途径使细胞能够感知并对不利的环境变化做出反应。亚致死剂量的不同应激(ROS、热休克、环境毒素)可以诱导适应性生存反应，使细胞和生物体在面对不利刺激时继续正常工作。适应性反应是由一组强大的抗凋亡基因(热休克蛋白(HSP)、抗氧化剂)介导的，它们可以保护细胞免受不同的毒性应激，使细胞能够存活。适应性反应可以抵消应激对脂质、蛋白质和DNA的损伤，和/或提高对这种损伤的耐受性。如果适应性反应不能保护细胞，那么受损的细胞将通过凋亡和/或坏死性下垂来消除。 我们发现，在40℃诱导的适应性生存反应可以保护哺乳动物细胞免受ROS和43℃热休克等毒性应激的影响。除了热休克蛋白，抗氧化剂和内质网应激蛋白也被这种适应性反应上调。然而，在40℃下诱导的这种适应性反应背后的机制并不完全清楚。 长期目标：我们正在进行的研究旨在进一步阐明轻度耐热的细胞和分子基础，轻度耐热是暴露在40摄氏度的低、非致命温度下的细胞诱导的适应性生存反应。耐热性保护细胞免受各种环境压力的不利影响，我的假设是，40℃低剂量热应激预适应诱导了多种防御系统，保护细胞免受更具侵略性的压力和环境毒素的不利影响。细胞对压力和毒素的一种常见反应是增加ROS的产生，如超氧化物和过氧化氢。 我们的具体短期目标是： 1.确定在40℃下轻度热休克是否会增加ROS，从而诱导适应性生存反应。 2.建立Nrf2信号通路在适应性生存反应(40C)中的作用，以及该信号通路与内质网应激和热休克因子1(HSF1)介导的应激反应之间的可能联系。 3.确定在40℃的预处理细胞中，在42-43℃时诱导细胞存活反应(内质网应激、自噬)和细胞死亡(凋亡)之间的阈值是否发生了变化。 了解细胞对应激环境的适应机制将为大量关于人类和野生动物暴露在有毒污染物中的研究提供信息，识别更敏感的毒理学风险评估生物标志物，并展示如何利用适应性生存反应的修复能力来保护和修复应激诱导的生物系统损伤。有了这些知识，新的策略(例如，增强内源性生存反应)将被开发出来，以保护生物免受有毒物质的伤害，并减缓或阻止我们老龄化人口的功能障碍。