Dietary restriction (DR) is defined as reduced food consumption without malnutrition and extends lifespan in organisms as diverse as yeast, roundworms, fruit flies and mammals. A less-well characterized but potentially more tangible benefit of DR is increased resistance to stress, including ischemia reperfusion injury to various organs in mammals. Currently no clinical applications of DR exist due to difficulty in adherence to restricted diets combined with the perception that long periods of DR are required for tangible benefits. We have recently shown that brief periods of DR lend significant protection against renal ischemia reperfusion injury in mice [8]. Acute renal injury due to ischemia is a major cause of morbidity and mortality in the clinic. The concept of preconditioning against ischemic damage is well-established, but the ability to do so by brief dietary intervention is novel. We refer collectively to short-term nutritional interventions with efficacy against ischemia reperfusion injury as dietary preconditioning. Effective regimens in mice include 2-4 weeks of 30% food reduction, 3 days of water-only fasting, and 1-2 weeks of isolated protein or essential amino acid deficiency in the absence of energy restriction. Here we propose to elucidate the nutritional triggers, nutrient sensors, and downstream effectors of dietary preconditioning in mice. In light of our finding that removal of even a single essential amino acid activated robust protection, we will test the requirement for the major amino acid sensor GCN2 using whole-body and kidney-specific GCN2 knockout mice. We will also test the requirement for upregulation of cytoprotective genes identified by transcriptional profiling. Finally, we will test the hypothesis that excess ROS generated during the metabolic shift to fat oxidation are required for upregulation of cytoprotective gene expression. We expect to identify nutritional requirements and downstream effectors of this novel form of preconditioning against renal ischemia reperfusion injury in mice. We also hope to identify the first mammalian gene required for acute stress resistance by DR. Our long-term goal is to develop brief nutritional interventions to precondition the body against acute stress in the clinic. Such clinical applications include ischemia reperfusion injury unavoidably incurred in a number of surgical procedures such as organ transplantation and cardiovascular surgery. PUBLIC HEALTH RELEVANCE: Dietary restriction (DR) has beneficial effects on metabolism and physiology in humans but is absent from clinical medicine because of notoriously low voluntary compliance rates. Our preliminary data demonstrate that the onset of benefits in mammals actually occurs quite rapidly - within days. Here we test the ability of short-term DR regimens to increase resistance to acute surgical stress in mice with the goal of moving rapid DR benefits to the clinic.