Protection against renal ischemic injury by short term dietary restriction

描述（由申请人提供）：饮食限制（DR）定义为减少食物消耗而不营养不良，并延长酵母、蛔虫、果蝇和哺乳动物等多种生物的寿命。DR的一个不太明确但可能更切实的好处是增加对应激的抵抗力，包括对哺乳动物各种器官的缺血再灌注损伤。目前，由于难以坚持限制饮食，加上认为需要长期DR才能获得切实的益处，因此不存在DR的临床应用。我们最近发现，短暂的DR可显著保护小鼠免受肾缺血再灌注损伤[8]。缺血引起的急性肾损伤是临床发病率和死亡率的主要原因。预处理对缺血性损伤的概念是公认的，但通过简单的饮食干预来做到这一点的能力是新颖的。我们将对缺血再灌注损伤有效的短期营养干预统称为“饮食预处理”。在小鼠中的有效方案包括2-4周的30%食物减少，3天的仅水禁食，和1-2周的分离的蛋白质或必需氨基酸缺乏，在没有能量限制的情况下。在这里，我们建议阐明营养触发器，营养传感器，和下游效应的饮食预处理小鼠。鉴于我们的发现，即使去除单个必需氨基酸也会激活强大的保护作用，我们将使用全身和肾脏特异性GCN 2敲除小鼠测试对主要氨基酸传感器GCN 2的需求。我们还将测试通过转录谱鉴定的细胞保护基因上调的要求。最后，我们将测试的假设，过量的活性氧代谢过程中产生的脂肪氧化的细胞保护基因表达的上调。我们希望确定这种新形式的预处理对小鼠肾缺血再灌注损伤的营养需求和下游效应。我们还希望通过DR确定第一个急性应激抗性所需的哺乳动物基因。我们的长期目标是开发简短的营养干预措施，以在临床上对急性应激进行身体预处理。此类临床应用包括在许多外科手术如器官移植和心血管手术中可避免地引起的缺血再灌注损伤。 公共卫生相关性：饮食限制（DR）对人类的新陈代谢和生理学有有益的影响，但由于自愿遵守率极低，因此在临床医学中缺乏。我们的初步数据表明，对哺乳动物的益处实际上发生得相当迅速-在几天内。在这里，我们测试了短期DR方案增加小鼠对急性手术应激的抵抗力的能力，目的是将快速DR的益处转移到临床。

DESCRIPTION (provided by applicant): 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.