In Vivo Regulation of Protein Turnover by Hormones

激素对蛋白质周转的体内调节

• 批准号: 8512150
• 负责人: K Sreekumaran Nair
• 金额: $ 14.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8512150
• 关键词: 8-Oxo-2' -Deoxyguanosine; ATP Synthesis Pathway; Address; Adverse effects; Aerobic Exercise; Age; American; Antioxidants; Asian Indian; Attenuated; Biological; Buffers; Caloric Restriction; Cells; Central obesity; Characteristics; Chemicals; Coupling; DNA; DNA biosynthesis; Data; Deoxyguanosine; Development; Diabetes Mellitus; Diet; Elderly; Energy Metabolism; European; Exercise; Exhibits; Fat-Restricted Diet; Fatty acid glycerol esters; Functional disorder; Funding; Gel; Genes; Health; Hormones; Immigrant; Individual; Infusion procedures; Insulin; Insulin Resistance; Intervention; Isotopes; Laboratories; Lipids; Measures; Metabolic Diseases; Methodology; Methods; Mitochondria; Mitochondrial DNA; Muscle; Muscle Proteins; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acids; Obesity; Oxidative Stress; Participant; Pharmaceutical Preparations; Phenylalanine; Physical activity; Placebos; Plasma; Plasma Proteins; Play; Population; Post-Translational Protein Processing; Predisposition; Prevalence; Process; Production; Protein Biosynthesis; Protein Isoforms; Proteins; Proteome; Reactive Oxygen Species; Regulation; Relative (related person); Reporting; Risk; Role; Seminal; Skeletal Muscle; Societies; Spottings; System; Transcript; Two-Dimensional Gel Electrophoresis; base; deamidation; density; improved; in vivo; insight; insulin sensitivity; insulin sensitizing drugs; novel; novel strategies; oxidation; oxidative DNA damage; oxidative damage; protein degradation; protein metabolism; public health relevance; research study; response; sex; therapy design

DESCRIPTION (provided by applicant): We will first determine whether people with high muscle mitochondrial capacity produce higher amount of reactive oxygen species (ROS) on consuming high fat diet and thus exhibit elevated cellular oxidative damage. We previously found that Asian Indian immigrants have high mitochondrial capacity in spite of severe insulin resistance. Somalians are another new immigrant population with rapidly increasing prevalence of diabetes. Both of these groups traditionally consume low caloric density diets, and we hypothesize that when these groups are exposed to high-calorie Western diets, they exhibit increased oxidative stress, oxidative damage, and insulin resistance. We will compare Asian Indians, Somalians, and NE Americans who are matched for age, BMI, and sex. We will measure ROS production in skeletal muscle following high fat meal. We will compare the oxidative damage to proteins, DNA, and lipids in these three populations following 2 weeks of high fat diet in comparison with low fat diet. We will determine if elevated levels of oxidative damage in these populations is accompanied by high mitochondrial capacity, higher ROS-emitting potential, and lower insulin sensitivity than NE. Secondly the proposal will apply a novel method developed in our laboratory to determine whether abdominally obese people with severe insulin resistance, high insulin levels, and oxidative stress accumulate old and damaged muscle and plasma proteins that may cause deleterious functional consequences. We will determine whether decreasing circulating insulin and oxidative stress by enhancing insulin sensitivity decreases the accumulation of old and damaged protein in muscle and plasma. We hypothesize that three different modes of enhancing insulin sensitivity act by different mechanisms to decrease the accumulation of old and damaged proteins and DNA oxidation. We expect caloric restriction (CR) to reduce oxidative stress by reducing ROS production and thus decrease oxidative damage to proteins and DNA. In contrast aerobic exercise increases ROS production but stimulates a robust antioxidant defense system. Furthermore, unlike CR we expect exercise to increase the synthesis of nascent proteins and turnover of old, damaged proteins. Insulin sensitizers reduce oxidative stress and enhance clearance of old and damaged protein. We will study abdominally obese people and compare them with lean participants to determine whether these insulin resistant people accumulate more damaged proteins and DNA in comparison with lean insulin sensitive people. We will then determine whether 16 weeks of aerobic exercise, caloric restriction and insulin sensitizers versus placebo will attenuate oxidative damage to proteins and DNA and improve insulin sensitivity. The proposed studies will be performed utilizing the state-of-the-art methods many of which were developed in our laboratory during the previous funding period. We expect the results from these studies to provide seminal insights into the underlying mechanism of insulin resistance and type 2 diabetes, in addition to demonstrating mechanisms by which a functional proteome is maintained in vivo. PUBLIC HEALTH RELEVANCE: The proposed experiments investigate the potential novel underlying mechanisms of rapidly expanding prevalence of diabetes and related health problems in the society. First specific aim is to determine whether more efficient mitochondria, the powerhouse of cell that produce chemical energy, causes adverse effects on DNA and protein when transitioning from a diet of low calorie content to that of high energy content. The second and third aims are to measure the accumulation of damaged and old proteins in muscle and plasma, using a novel methodology in obese and insulin resistant people and to determine how this potentially deleterious process is altered by aerobic exercise, caloric restriction, and medication that enhance insulin sensitivity and reduce high insulin levels.

描述（由申请人提供）：我们将首先确定肌肉线粒体能力高的人是否会在消耗高脂饮食的情况下产生更高量的活性氧（ROS），从而表现出升高的细胞氧化损伤。我们以前发现，尽管具有严重的胰岛素抵抗，但亚洲印度移民的线粒体能力很高。索马里人是另一个新的移民人口，糖尿病患病率迅速增加。这两组传统上都消耗低热量密度饮食，我们假设当这些组暴露于高热量西方饮食时，它们会表现出增加的氧化应激，氧化损伤和胰岛素抵抗。我们将比较与年龄，BMI和性别相匹配的亚洲印第安人，索马里人和NE的美国人。高脂餐后，我们将测量骨骼肌中的ROS产生。与低脂饮食相比，我们将在这三个种群中比较这三个种群中蛋白质，DNA和脂质的氧化损伤。我们将确定这些人群中氧化损伤水平的升高是否伴随着高线粒体能力，更高的ROSSTITTION潜力和胰岛素敏感性较低。其次，该提案将采用在我们的实验室中开发的一种新方法，以确定具有严重胰岛素抵抗，高胰岛素水平和氧化应激的腹部肥胖者是否会累积旧的和受损的肌肉和血浆蛋白，从而导致有害功能后果。我们将通过增强胰岛素敏感性来降低循环胰岛素和氧化应激的减少，从而降低肌肉和血浆中旧蛋白质和受损蛋白质的积累。我们假设三种不同的增强胰岛素敏感性的模式通过不同的机制来减少旧蛋白和受损蛋白质和DNA氧化的积累。我们期望热量限制（CR）通过减少ROS产生，从而减少氧化应激，从而减少对蛋白质和DNA的氧化损伤。相反，有氧运动增加了ROS的产生，但刺激了强大的抗氧化防御系统。此外，与CR不同，我们期望运动会增加新生蛋白的合成和旧蛋白质受损的蛋白质的营业额。胰岛素敏化剂可减少氧化应激，并增强旧蛋白质和受损蛋白质的清除。我们将研究腹部肥胖的人，并将他们与精益参与者进行比较，以确定与瘦胰岛素敏感的人相比，这些耐胰岛素的人是否积累了更多受损的蛋白质和DNA。然后，我们将确定16周的有氧运动，热量限制和胰岛素敏化剂与安慰剂是否会减轻对蛋白质和DNA的氧化损害，并提高胰岛素敏感性。拟议的研究将利用最先进的方法进行，其中许多方法是在上一个资金期间在我们的实验室中开发的。我们期望这些研究的结果能够为胰岛素抵抗和2型糖尿病的潜在机制提供精确见解，此外还证明了在体内维持功能蛋白质组的机制。 公共卫生相关性：拟议的实验研究了社会中糖尿病和相关健康问题快速扩大的潜在新型潜在基础机制。第一个具体目的是确定在从低热量含量的低热能饮食过渡到高能量含量的饮食时，更有效的线粒体是产生化学能的细胞的动力，会对DNA和蛋白质产生不利影响。第二和第三目的是使用肥胖和抗胰岛素耐药者的新方法来测量肌肉和血浆中受损和旧蛋白的积累，并确定有氧运动，热量限制和药物如何改变这种潜在有害过程，从而增强胰岛素敏感性并降低高胰岛素水平。