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

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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.