Reference number : GC-2017-Q1-02834, amendment number : , agreement type : G, recipient legal name : Averill-Bates, Diana (Université du Québec à Montréal), recipient country : CA, recipient province : nan, recipient city : Quebec|Québec, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : 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 40&deg;C protected mammalian cells against toxic stresses such as ROS and 43&deg;C 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 40&deg;C 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 40&deg;C. Thermotolerance protects cells against adverse effects of a variety of environmental stresses and my hypothesis is that preconditioning by low-dose heat stress at 40&deg;C 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 40&deg;C increases ROS, which then induce the adaptive survival response. 
2. Establish the role of the Nrf2 signaling pathway in the adaptive survival response (40&deg;C) 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 42-43&ordm;C is altered in preconditioned cells at 40&deg;C. 
 
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., program purpose french : 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 40&deg;C protected mammalian cells against toxic stresses such as ROS and 43&deg;C 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 40&deg;C 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 40&deg;C. Thermotolerance protects cells against adverse effects of a variety of environmental stresses and my hypothesis is that preconditioning by low-dose heat stress at 40&deg;C 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 40&deg;C increases ROS, which then induce the adaptive survival response. 
2. Establish the role of the Nrf2 signaling pathway in the adaptive survival response (40&deg;C) 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 42-43&ordm;C is altered in preconditioned cells at 40&deg;C. 
 
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., agreement title english : Cellular and molecular studies of adaptive survival responses induced by mild heat stress at 40°C in mammalian cells, agreement title french : Cellular and molecular studies of adaptive survival responses induced by mild heat stress at 40°C in mammalian cells, agreement number : RGPIN, agreement value : 355000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2022-2023), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2022-2023), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada