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

应激反应通路允许细胞感知和应对不利的环境变化。亚致死剂量的不同应激（活性氧（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功能。适应性反应是由一组核心的强大的抗凋亡基因（热休克蛋白（Hsp），抗氧化剂）介导的，这些基因保护细胞免受各种毒性应激并使细胞存活。适应性反应可以抵消压力引起的对脂质、蛋白质和DNA的损害，并/或增加对这种损害的耐受性。如果适应性反应不能保护细胞，那么受损细胞将通过凋亡和/或坏死而被消灭。***我们发现，在40C诱导的适应性生存反应可以保护哺乳动物细胞免受ROS和43C热休克等毒性应激。除了热休克蛋白外，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，这种在40℃下诱导的适应性反应的机制尚不完全清楚。******长期目标：我们正在进行的研究旨在进一步阐明轻度耐热性的细胞和分子基础，轻度耐热性是暴露于40℃的低、非致死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，通过40摄氏度的低剂量热应激进行预处理，可诱导多种防御系统，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共同反应是增加活性氧的产生，如超氧化物和H2O2。******我们的具体短期目标是：***1。确定40℃的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，以及该通路与内质网应激和Hsf1（热休克因子1）介导的应激反应之间的可能联系。* * * 3。确定在42-43℃条件下诱导细胞存活反应（内质网应激、自噬）和细胞死亡（凋亡）之间的阈值是否在40℃条件下发生改变。******了解细胞适应压力环境的机制将为人类和野生动物暴露于有毒污染物的大量调查提供信息，为毒理学风险评估确定更敏感的生物标志物，并展示如何利用适应性生存反应的愈合能力来保护和修复压力引起的生物系统损伤。有了这些知识，新的策略（例如，提高内源性生存反应）将被开发出来，以保护生物体免受有毒物质的侵害，并减缓或停止我们人口老龄化的功能障碍。

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.