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

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）可导致适应性反应，允许细胞和生物体在面对不利刺激时继续正常功能。适应性反应似乎是由一组强大的抗凋亡基因（如热休克蛋白，抗氧化剂），保护免受不同的毒性应激，使细胞存活的核心组介导的。适应性反应可以抵消应激诱导的脂质、蛋白质和DNA损伤，和/或增加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被消除。近年来，我们研究了在轻度发热范围温度（40 ℃）下诱导的适应性反应，以及其对毒性应激（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。我们的研究计划的长期目标是确定在40 ℃的低的非致死温度下诱导的耐热性的适应性生存反应的细胞和分子基础。我们的假设是：在40 ℃下通过非致死性热应激对细胞进行预处理是一种适应性反应，可能涉及诱导多种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，我们将集中在以下短期目标：1.研究活性氧在40 ℃诱导热耐受中的作用; 2.确定热适应（40 ℃）是否改变应激（活性氧和热休克）诱导自噬和凋亡之间的阈值; 3.研究热适应（40 ℃）是否改变应激诱导自噬和凋亡之间的阈值。确定在40 ℃热适应发展过程中基因表达的变化。对不同压力诱导的死亡/生存途径的细胞和分子基础的研究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愈合能力来保护人类和其他生物物种免受有毒和环境压力的有害影响。

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.