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，以及活性物种和疾病之间的联系，被普遍认为存在于教科书和流行媒体的领域。线粒体和能量产生之间的联系在初中学生中普遍受到重视。普通公众可能不太了解线粒体和钙(包括信号)、自由基或细胞死亡之间的联系，但每一种都有超过10,000条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随意联系--以及一些具体的实验支持--但据我们所知，没有系统的研究来弥合这一根本差距。弥合这一差距是理解环境-基因相互作用的核心，因为次优的膳食大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来源。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和蛋白质组生物标记物，用于饮食中脂肪和碳水化合物亚类的摄取，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以下假设：饮食对线粒体的相关影响与饮食相关的疾病风险变化有关。提出了五个目标。目的1确定饮食中脂肪酸和碳水化合物组成的变化对线粒体生理学的影响目标2确定饮食中脂肪酸和碳水化合物组成的变化对血浆代谢组和蛋白质组的影响目标3和4：确定在护士健康研究中嵌套的先前概述的病例对照研究中，坚持/存在每种饮食、饮食组成和线粒体特性预测II型糖尿病(AIM 3)和乳腺癌(AIM 4)的程度。目标5：提供参与者血液代谢和蛋白质组成分的电子档案，可重复挖掘以用于未来新假说的测试。拟议的研究直接响应了RFA和NIH进一步的一般目标，即侧重于健康和早期干预，而不是晚期疾病。

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.