Macronutrients, Mitochondria and Blood Metabolome/Proteome Disease Risk Profiles

常量营养素、线粒体和血液代谢组/蛋白质组疾病风险概况

• 批准号: 7485221
• 负责人: BRUCE S KRISTAL
• 金额: $ 42.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7485221
• 关键词: Adherence; Affect; Age; Algorithms; Animal Feed; Animals; Antioxidants; Appendix; Archives; Area; Asses; Binding; Biochemical; Biochemistry; Bioinformatics; Biological; Biological Markers; Biomarker of Dietary Intake; Blood; Body Temperature; Calcium; Calcium Signaling; Caloric Restriction; Carbohydrates; Cardiovascular system; Catabolism; Cell Death; Cerebrovascular Disorders; Cholecystokinin; Chronic; Chronic Disease; Classification; Cluster Analysis; Color; Computers; Condition; Consumption; Corticosterone; Coupled; Data; Databases; Degenerative Disorder; Dehydroepiandrosterone Sulfate; Detection; Development; Diabetes Mellitus; Diet; Diet Records; Disease; Drops; Drug Metabolic Detoxication; Early Intervention; Eating; Electrodes; Electron Transport; Electronics; Electrophoresis; Energy Intake; Environment; Epidemiologic Studies; Equilibrium; Expert Systems; Fatty Acids; Fatty acid glycerol esters; Female; Food; Fractionation; Free Radicals; Functional disorder; Funding; Future; Gene Chips; General Population; Generations; Genes; Glucose; Glutathione Disulfide; Glycemic Index; Goals; Gold; Grant; Growth; Guinea; Health; High Pressure Liquid Chromatography; Hormonal; Hormones; Human; Incidence; Individual; Inflammation; Insulin; Intake; Intervention; Ions; Knowledge; Laboratories; Lead; Learning; Left; Life; Link; Lipids; Literature; Liver Mitochondria; Logic; Longevity; Macronutrients Nutrition; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Measurable; Measurement; Measures; Messenger RNA; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Methodology; Methods; Minerals; Mining; Mitochondria; Modeling; Molecular Profiling; Molecular Weight; Morbidity - disease rate; Mus; Nature; Neoplasms; Nerve Degeneration; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Normal Horse Serum; Nurses' Health Study; Nutrient; Obesity; Oxidants; Oxidation-Reduction; Participant; Pathogenesis; Pattern; Pattern Recognition; Physiological; Physiological Processes; Physiology; Plague; Plasma; Population; Population Study; Principal Component Analysis; Principal Investigator; Production; Property; Protein Microchips; Proteins; Proteome; Proteomics; Protocols documentation; PubMed; Purines; Range; Rattus; Reactive Oxygen Species; Reading; Recycling; Relative (related person); Relative Risks; Research Personnel; Resistance; Resolution; Resources; Respiration; Respiratory Chain; Risk; Rodent; Role; Rotation; Sampling; Scheme; Serotyping; Serum; Serum Proteins; Signal Transduction; Societies; Staging; Standards of Weights and Measures; State Interests; Statistically Significant; System; Techniques; Technology; Testing; Textbooks; Thioctic Acid; Time; Tocopherols; Training; Treatment Protocols; Tryptophan Metabolism Pathway; Tyrosine; United States National Institutes of Health; Validation; Variant; Vitamins; Water; Work; age related; ascorbate; base; cancer type; case control; cohort; compound 20; concept; cost; day; detector; dietary constituent; dihydrolipoic acid; disorder risk; environmental stressor; feeding; gene environment interaction; glucose metabolism; high school; human disease; human study; innovation; interest; male; malignant breast neoplasm; metabolomics; mitochondrial dysfunction; mortality; nano; new technology; nonhuman primate; oxidation; prevent; programs; protein metabolite; purine; reproductive hormone; response; saturated fat; scale up; sensor; size; small molecule; success; theories; tool; transcription factor

DESCRIPTION (provided by applicant): Links between diet and human disease, and between reactive species and disease, are so commonly considered as to lie in the realm of textbooks and the popular press. Links between mitochondria and energy production are generally appreciated by junior high school. Links between mitochondria and calcium (including signaling), free radicals, or cell death may be less known to the general public, but each has in excess of 10,000 PubMed citations. However, despite broad and strong theoretical considerations supporting casual connections between diet effects on mitochondria and diet effects on disease - and some specific experimental support - there are, to our knowledge, no systematic studies that bridge this fundamental gap. Bridging this gap is central to understanding environment-gene interactions, as suboptimal dietary macronutrient choices are arguably the major environmental stressor in individuals living in Western societies. We therefore propose to bridge this gap using an interdisciplinary, product-development approach to discover and confirm innovative plasma metabolomic and proteomic biomarkers for dietary intake of subclasses of fats and carbohydrates, and for their effects on mitochondrial (dys)function. We will then validate these markers by using them to test the hypothesis that diet-associated effects on mitochondria are linked to diet-associated changes in disease risk. Five Aims are proposed. Aim 1 To determine the effects of dietary changes in fatty acid and carbohydrate composition on mitochondrial physiology Aim 2 To determine the effects of dietary changes in fatty acid and carbohydrate composition on the plasma metabolome and proteome Aims 3 and 4: To determine the extent to which adherence to/presence of each diet, dietary constituent, and mitochondrial property predict type II diabetes (Aim 3) and breast cancer (Aim 4) in previously profiled case control studies nested within the Nurses' Health Study Aim 5: To provide an electronic archive of the metabolomic and proteomic constituents of the blood of participants that could be repeatedly mined for future testing of new hypotheses. The proposed studies are directly responsive to the RFA and further general NIH goals of focusing on health and early interventions rather than late stage disease.

描述（由申请人提供）： 饮食与人类疾病之间以及反应性物种与疾病之间的联系被普遍认为存在于教科书和大众媒体的领域中。初中生普遍认识到线粒体和能量产生之间的联系。线粒体与钙（包括信号传导）、自由基或细胞死亡之间的联系可能不太为公众所知，但每种联系都有超过 10,000 次 PubMed 引用。然而，尽管广泛而有力的理论考虑支持饮食对线粒体的影响和饮食对疾病的影响之间的偶然联系——以及一些具体的实验支持——但据我们所知，还没有系统的研究能够弥合这一根本差距。弥合这一差距对于理解环境与基因相互作用至关重要，因为次优饮食大量营养素的选择可以说是生活在西方社会的个人的主要环境压力源。因此，我们建议使用跨学科的产品开发方法来弥补这一差距，以发现和确认创新的血浆代谢组和蛋白质组生物标志物，用于膳食脂肪和碳水化合物亚类的摄入，以及它们对线粒体（功能障碍）的影响。然后，我们将通过使用这些标记来验证以下假设：饮食对线粒体的影响与饮食相关的疾病风险变化有关，从而验证这些标记。提出了五个目标。目标 1 确定脂肪酸和碳水化合物组成的饮食变化对线粒体生理学的影响 目标 2 确定脂肪酸和碳水化合物组成的饮食变化对血浆代谢组和蛋白质组的影响 目标 3 和 4：确定坚持/存在每种饮食、膳食成分和线粒体特性在多大程度上预测 II 型糖尿病（目标 3）和乳腺癌 （目标 4）在先前描述的病例对照研究中，嵌套在护士健康研究目标 5 中：提供参与者血液的代谢组和蛋白质组成分的电子档案，可以重复挖掘该档案以供将来测试新假设。拟议的研究直接响应 RFA 和 NIH 关注健康和早期干预而非晚期疾病的总体目标。