Cellular and molecular studies of adaptive survival responses: thermotolerance induced at 40C

适应性生存反应的细胞和分子研究：40°C 诱导的耐热性

• 批准号: 36725-2011
• 负责人: AverillBates, Diana
• 金额: $ 2.91万
• 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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=568772
• 关键词: Cellular; molecular; studies; adaptive; survival

Stress response pathways allow cells to sense and respond to adverse environmental changes. Exposure to sub-lethal doses of different stresses (e.g. reactive oxygen species (ROS), heat shock, radiation) can lead to adaptive responses that allow cells and organisms to continue normal function in the face of an adverse stimulus. Adaptive responses appear to be mediated by a core group of powerful anti-apoptotic genes (e.g. Hsps, antioxidants) that protect against diverse toxic stresses and enable the cell to survive. The 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 will be eliminated by apoptosis. During recent years, we have studied the adaptive response induced at a mild fever range temperature (40C), and its cytoprotective effect against toxic stresses (e.g. heat shock, ROS). However, the cellular and molecular basis of this adaptive response is not clearly understood. The long-term goals of our research program are to determine the cellular and molecular basis of the adaptive survival response of thermotolerance induced at a low, non-lethal temperature of 40C. Our Hypothesis is: Preconditioning of cells by non-lethal heat stress at 40C is an adaptive response that likely involves induction of multiple defenses to protect cells against adverse effects of different stresses. To achieve these goals, we will focus on the following Short-term objectives: 1.To investigate the role of ROS in the induction thermotolerance at 40C; 2.To determine whether thermal adaption (40C) alters the threshold between induction of autophagy and apoptosis by stress (ROS and heat shock); 3. To determine changes in gene expression during development of thermal adaption at 40C. A search for the cellular and molecular basis of death/survival pathways induced by different stresses could provide the basis for understanding environmental health problems, providing more sensitive biomarkers for toxicological risk assessment, and utilizing the healing capacity of adaptive responses to protect against deleterious effects of toxic and environmental stresses in humans and other living species.

应激反应途径使细胞能够感知和应对不利的环境变化。暴露于亚致死剂量的不同应激（例如活性氧（ROS）、热休克、辐射）可以导致适应性反应，使细胞和生物体在面对不利刺激时能够继续正常功能。适应性反应似乎是由一组强大的抗凋亡基因（例如热休克蛋白、抗氧化剂）介导的，这些基因可以抵御多种毒性应激并使细胞能够生存。适应性反应可以抵消应激引起的脂质、蛋白质和 DNA 损伤，和/或增加对此类损伤的耐受性。如果适应性反应不能保护细胞，那么受损的细胞就会通过凋亡而被消灭。近年来，我们研究了在轻度发烧范围温度（40℃）下诱导的适应性反应，及其针对毒性应激（例如热休克，ROS）的细胞保护作用。然而，这种适应性反应的细胞和分子基础尚不清楚。我们研究计划的长期目标是确定在 40°C 的非致命低温下诱导的耐热性适应性生存反应的细胞和分子基础。我们的假设是：通过 40°C 的非致命热应激对细胞进行预处理是一种适应性反应，可能涉及诱导多重防御以保护细胞免受不同应激的不利影响。为了实现这些目标，我们将重点关注以下短期目标： 1.研究ROS在40C诱导耐热性中的作用； 2.确定热适应（40℃）是否改变应激（ROS和热休克）诱导自噬和凋亡之间的阈值； 3.确定40℃热适应发展过程中基因表达的变化。寻找不同应激引起的死亡/生存途径的细胞和分子基础可以为理解环境健康问题提供基础，为毒理学风险评估提供更敏感的生物标志物，并利用适应性反应的治愈能力来防止有害影响人类和其他生物物种的毒性和环境压力。