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

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: 36725-2010
• 负责人: Averill(Bates), Diana
• 金额: $ 2.4万
• 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: 2010
• 资助国家: 加拿大
• 起止时间: 2010-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=450680
• 关键词: Cellular; molecular; studies; adaptive; survival

Low dose chronic exposure to different stresses (e.g. toxic compounds, radiation) can lead to adaptive responses that allow cells and organisms to continue normal function in the face of an adverse stimulus. Adaptive responses often involve changes in gene and protein expression, including induction of defenses to enable cells to survive. Organisms have developed an elaborate system of defense molecules (e.g. antioxidants, heat shock proteins, anti-apoptosis proteins) and cell survival signaling pathways to counteract various toxic and environmental stresses. The adaptive response could counteract stress-induced damage to lipids, proteins and DNA, and/or increase tolerance to such damage. If the adaptive response does not counteract the adverse exposure, then damaged cells will be eliminated by death processes such as apoptosis. During recent years, we have studied thermotolerance induced at a mild, fever range (40oC), and its ability to protect cells against toxic stresses (e.g. heat shock, oxidative stress). However, the cellular and molecular basis of this adaptive response induced at 40°C is not clearly understood. The Long Term Goals of our research program are to determine the cellular and molecular basis of (i) heat shock (42-45°C)-induced toxicity, and of (ii) the adaptive survival response of thermotolerance induced at 40°C. Our Short Term objectives are: 1. To examine the role of thermotolerance (40°C) during induction of ER stress and autophagy by heat shock (42-45°C). 2. To investigate the protective role of thermotolerance (40°C) against heat shock-induced pro-apoptosis protein-protein interactions between Bcl-2 proteins. 3. To perform functional studies of Bcl-2 expression on cellular sensitivity to heat shock. 4. To analyse changes in gene expression during development of thermotolerance at 40°C. It is important to clarify the cellular and molecular mechanisms underlying adaptation to stressful environments. This could provide the basis for understanding environmental health problems, performing toxicological risk assessment, and clinically utilizing the healing capacity of adaptive responses to protect against deleterious effects of toxic and environmental stresses in humans and other living species.

低剂量慢性暴露于不同的压力(如有毒化合物、辐射)可导致适应性反应，使细胞和生物体在面对不利刺激时继续正常运作。适应性反应通常涉及基因和蛋白质表达的变化，包括诱导防御以使细胞存活。生物体已经形成了一套复杂的防御分子系统(如抗氧化剂、热休克蛋白、抗凋亡蛋白)和细胞生存信号通路，以对抗各种毒性和环境压力。这种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抵消不利的暴露，那么受损的细胞将通过死亡过程(如细胞凋亡)来消除。近年来，我们研究了在温和的发热范围(40摄氏度)下诱导的耐热性，以及它保护细胞免受毒性应激(如热休克、氧化应激)的能力。然而，这种在40°C诱导的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(I)热休克(42-45°C)诱导的毒性和(Ii)在40°C诱导的耐热性的适应性生存反应的细胞和分子基础。我们的短期目标是：1.研究耐热性(40°C)在热休克(42-45°C)诱导内质网应激和自噬过程中的作用。2.探讨耐热性(40℃)对热休克诱导的促凋亡蛋白-蛋白间相互作用的保护作用。3.研究热休克后细胞对Bcl一2表达的影响。4.分析40℃下植物耐热性发育过程中基因表达的变化，阐明植物对胁迫环境适应的细胞和分子机制是非常重要的。这可能为理解环境健康问题，进行毒理学风险评估，并在临床上利用适应性反应的修复能力来保护人类和其他生物免受有毒和环境应激的有害影响提供基础。