Macronutrients, Mitochondria and Blood Metabolome/Proteome Disease Risk Profiles

描述（由申请人提供）： 饮食和人类疾病之间的联系，以及反应性物种和疾病之间的联系，通常被认为是教科书和大众媒体的领域。线粒体和能量产生之间的联系通常被初中所认识。线粒体和钙（包括信号），自由基或细胞死亡之间的联系可能不太为公众所知，但每个都有超过10，000个PubMed引文。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因果关系-以及一些特定的实验支持-据我们所知，没有系统的研究可以弥合这一根本性的差距。弥合这一差距是理解环境-基因相互作用的核心，因为次优的膳食宏量营养素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合这一差距，以发现和确认创新的血浆代谢组学和蛋白质组学生物标志物，用于脂肪和碳水化合物亚类的膳食摄入，以及它们对线粒体（dys）功能的影响。然后，我们将通过使用这些标记来验证饮食对线粒体的影响与饮食相关的疾病风险变化有关的假设。提出了五个目标。目的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的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的3和4：为了确定每种饮食、饮食成分、和线粒体特性预测II型糖尿病（目标3）和乳腺癌（目标4）在以前的病例对照研究嵌套在护士健康研究目标5：提供参与者血液代谢组学和蛋白质组学成分的电子档案，可重复挖掘，用于未来新假设的测试。拟议的研究直接响应RFA和进一步关注健康和早期干预而不是晚期疾病的NIH总体目标。

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.