Genetic Control of Metabolic Flux in Response to Diet

对饮食反应的代谢流的遗传控制

基本信息

批准号：
10649513
负责人：
Alan D Attie
金额：
$ 150万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649513
关键词：
Adipose tissue Affect American Heart Association Animal Model Automobile Driving Biological Markers Biological Models Body Weight Candidate Disease Gene Carbohydrate Metabolism Pathway Carbohydrates Chromosome Mapping Clinical Clinical Markers Clinical Research Consensus Data Diet Diet Research Dietary Intervention Distal Eating Fatty acid glycerol esters Gene Expression Gene Expression Regulation Genes Genetic Genetic Determinism Genetic Markers Genetic Screening Genetic Variation Genetic study Genomic Segment Genotype Goals Health Human Inbred Strains Mice Individual Individual Differences Insulin Resistance Intestines Isotope Labeling Link Lipids Lipoproteins Liver Mammals Maps Mass Spectrum Analysis Measurement Measures Mediating Mediation Mediator Metabolic Metabolic Control Metabolic Diseases Metabolic Marker Metabolic Pathway Metabolism Modeling Molecular Mouse Strains Mus Muscle Nutrient Obesity Outcome Pathway interactions Persons Phenotype Physiological Physiology Plasma Play Population Prevalence Production Quantitative Trait Loci Recommendation Research Resolution Role SNP array Skeletal Muscle Small Intestines Synteny Testing Time Tissues Tracer Translating Validation Weight Gain blood lipid cardiometabolism density dietary experimental study gene discovery genetic architecture genetic variant genome wide association study genomic locus glucose tolerance gut microbiome gut microbiota human model insulin secretion insulin sensitivity interest ketogentic lean body mass lipid metabolism metagenomic sequencing microbiome model organism molecular marker molecular phenotype mouse model personalized medicine predictive marker protein metabolism response stable isotope trait whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Despite many years of research in humans and model organisms, there remains no clear consensus about which diet is most compatible with human health. However, the premise of this statement is that a single diet is ideal for everyone. Yet, among humans, there is a wide range in metabolic response to various diets, including body weight, glucose tolerance, and plasma lipids. Genetically diverse mice show this same metabolic variability, suggesting that genetics plays a key role in driving diet-responsiveness. In addition, the microbiome in both humans and mice contributes to diet responsiveness through its metabolism of dietary nutrients and production of potent metabolites. The premise of this project is that genetic interactions with diet and the gut microbiome affect metabolic health. Using an outbred mouse model system that has as much genetic diversity as the entire human population, the Diversity Outbred population, we will genetically map the gene loci that interact with diet and the microbiome to affect cardiometabolic phenotypes. We will test two diets, a low-fat/high carbohydrate diet and a high-fat/low carbohydrate diet. The mice will be phenotyped for glucose tolerance, insulin resistance, weight gain, and circulating levels of lipids and metabolites. Using 15 stable isotope tracers, we will conduct metabolic flux measurements using mass spectrometry-based isotopomer analysis, enabling us to interrogate the major pathways of carbohydrate, lipid, and protein metabolism in multiple tissues. This will be the first time metabolic flux has been subjected to a genetic screen. We will also map gut microbial composition, and gene regulation in key metabolic tissues: liver, adipose, muscle and intestine. These studies will deliver comprehensive genetic maps of these phenotypes. Through the identification of phenotypes that co-map, we will perform mediation analysis to construct causal networks that link gene loci, metabolites, microbiome taxa and physiological phenotypes. We will prioritize loci that are syntenic to human loci with significant metabolic associations in GWAS. These results will provide metabolic markers that can help predict an individual’s metabolic response to specific diets, the first step towards matching diets to individuals.

项目概要/摘要尽管对人类和模式生物进行了多年的研究，但对于哪种生物体仍然没有明确的共识饮食最符合人体健康，但这种说法的前提是单一饮食才是理想的。然而，人类对各种饮食（包括身体）的代谢反应存在很大差异。体重、葡萄糖耐量和血脂的遗传多样性小鼠表现出相同的代谢变异性，表明遗传学在驱动饮食反应方面发挥着关键作用此外，两者中的微生物组也发挥着关键作用。人类和小鼠通过饮食营养物质的代谢和生产来促进饮食反应该项目的前提是饮食和肠道微生物组的遗传相互作用。使用具有与整个小鼠一样多的遗传多样性的远交小鼠模型系统。人类群体，多样性远交群体，我们将对与饮食相互作用的基因位点进行基因图谱以及影响心脏代谢表型的微生物组我们将测试两种饮食，一种是低脂肪/高碳水化合物饮食。以及高脂肪/低碳水化合物饮食对小鼠进行葡萄糖耐量、胰岛素抵抗的表型分析。我们将使用 15 种稳定同位素示踪剂来进行体重增加以及脂质和代谢物的循环水平。使用基于质谱的同位素分析进行代谢通量测量，使我们能够询问多个组织中碳水化合物、脂质和蛋白质代谢的主要途径这将是首次。我们还将对肠道微生物组成和基因进行遗传筛选。这些研究将在关键代谢组织（肝脏、脂肪、肌肉和肠道）中进行调节。通过识别共同绘制的表型，我们获得了这些表型的综合遗传图谱。将进行中介分析以构建连接基因位点、代谢物、微生物组分类群的因果网络我们将优先考虑与具有显着代谢的人类基因座同线性的基因座。这些结果将提供有助于预测个体的代谢标记。对特定饮食的代谢反应，这是将饮食与个人相匹配的第一步。