Grant: Discovery Grants Program - Individual

Stress response pathways allow cells to sense and respond to adverse environmental changes. Sub-lethal doses of different stresses (reactive oxygen species (ROS), heat shock, environmental toxins) can induce adaptive survival responses that allow cells and organisms to continue normal function in the face of an adverse stimulus. Adaptive responses are mediated by a core group of powerful anti-apoptotic genes (heat shock proteins (Hsp), antioxidants) that protect against diverse toxic stresses and enable the cell to survive. An 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 would be eliminated by apoptosis and/or necroptosis. We found that an adaptive survival response induced at 40C protected mammalian cells against toxic stresses such as ROS and 43C heat shock. In addition to Hsps, antioxidants and ER stress proteins were upregulated by this adaptive response. However, mechanisms underlying this adaptive response induced at 40C are not entirely understood. Long-term goals : Our ongoing research aims to further clarify the cellular and molecular basis of mild thermotolerance, an adaptive survival response induced in cells exposed to a low, non-lethal temperature of 40C. Thermotolerance protects cells against adverse effects of a variety of environmental stresses and my hypothesis is that preconditioning by low-dose heat stress at 40C induces multiple defense systems that protect cells against adverse effects of more aggressive stresses and environmental toxins. A common response of cells to stresses and toxins is increased production of ROS such as superoxide and H 2 O 2 . Our specific short-term objectives are to: 1. Determine whether mild heat shock at 40C increases ROS, which then induce the adaptive survival response. 2. Establish the role of the Nrf2 signaling pathway in the adaptive survival response (40C) and possible links between this pathway and the ER stress- and Hsf1 (heat shock factor 1)-mediated stress responses. 3.Determine if the threshold between induction of cell survival responses (ER stress, autophagy) and cell death (apoptosis) at 42-43ºC is altered in preconditioned cells at 40C. Understanding of mechanisms involved in cellular adaptation to stressful environments will inform the multitude of investigations on exposure of humans and wildlife to toxic pollutants, identify more sensitive biomarkers for toxicological risk assessment and demonstrate how to utilize the healing capacity of the adaptive survival response to protect against and repair stress-induced damage to biological systems. Armed with this knowledge, novel strategies (e.g. boost endogenous survival responses) will be developed to protect living organisms against toxic agents and to slow or halt dysfunction in our aging population.