Grant: Discovery Grants Program - Individual

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.