Protection against renal ischemic injury by short term dietary restriction

短期饮食限制可预防肾缺血性损伤

• 批准号: 8286909
• 负责人: JAMES R. MITCHELL
• 金额: $ 31.82万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286909
• 关键词: Acute; Acute Kidney Failure; Adherence; Amino Acids; Antioxidants; Caloric Restriction; Calories; Carbohydrates; Cardiovascular Surgical Procedures; Clinic; Clinical Medicine; Cytoprotection; Data; Diet; Dietary Intervention; Dose; Drosophila genus; Energy Metabolism; Essential Amino Acids; Excision; Fasting; Fatty acid glycerol esters; Food; Gene Expression; Generations; Genes; Goals; Human; Injury; Ischemia; Kidney; Knockout Mice; Light; Longevity; Malnutrition; Mammals; Metabolic; Metabolism; Methods; Mitochondria; Morbidity - disease rate; Mus; Nematoda; Nutrient; Nutritional; Nutritional Requirements; Operative Surgical Procedures; Organ; Organ Transplantation; Organism; Pathway interactions; Perception; Phosphorylation; Physiology; Predisposition; Production; Proteins; Reactive Oxygen Species; Regimen; Reperfusion Injury; Resistance; Signal Transduction; Stress; Testing; Toxin; Translations; Up-Regulation; Water; Work; Yeasts; acute stress; clinical application; deprivation; derepression; dietary restriction; food consumption; food restriction; mortality; novel; oxidation; preconditioning; prevent; public health relevance; renal ischemia; response; sensor

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.

描述（由申请人提供）：饮食限制（DR）被定义为减少食物消耗而不导致营养不良，并延长酵母、蛔虫、果蝇和哺乳动物等多种生物体的寿命。 DR 的一个不太明确但可能更明显的好处是增强对压力的抵抗力，包括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，并且人们认为需要长期的 DR 才能获得切实的益处，因此 DR 尚无临床应用。我们最近表明，短暂的 DR 对小鼠肾缺血再灌注损伤具有显着的保护作用 [8]。缺血引起的急性肾损伤是临床发病和死亡的主要原因。针对缺血性损伤进行预处理的概念已经很成熟，但通过简短的饮食干预来实现这一点的能力是新颖的。我们将有效对抗缺血再灌注损伤的短期营养干预措施统称为“饮食预处理”。对小鼠的有效治疗方案包括 2-4 周减少 30% 的食物，3 天禁食，以及 1-2 周在不限制能量的情况下缺乏分离蛋白或必需氨基酸。在这里，我们建议阐明小鼠饮食预处理的营养触发因素、营养传感器和下游效应器。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 GCN2 敲除小鼠来测试对主要氨基酸传感器 GCN2 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，我们将检验以下假设：代谢转变为脂肪氧化过程中产生的过量 ROS 是上调细胞保护基因表达所必需的。我们期望确定这种针对小鼠肾缺血再灌注损伤的新型预处理的营养需求和下游效应器。我们还希望通过 DR 鉴定出第一个抵抗急性应激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，使身体在临床上免受急性压力的影响。此类临床应用包括在器官移植和心血管手术等许多外科手术中不可避免地发生的缺血再灌注损伤。 公共健康相关性：饮食限制（DR）对人类的新陈代谢和生理机能有有益影响，但由于众所周知的自愿依从率低而在临床医学中缺失。我们的初步数据表明，哺乳动物的获益实际上发生得相当快——几天之内。在这里，我们测试了短期 DR 方案增强小鼠对急性手术应激的抵抗力的能力，目的是将快速 DR 益处推向临床。