PROJECT 2 - Lipoproteins, oxidataive damage, and responses to diet

项目 2 - 脂蛋白、氧化损伤和饮食反应

• 批准号: 7025632
• 负责人: David L. Rainwater
• 金额: $ 21.01万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7025632
• 关键词: age difference; animal genetic material tag; apolipoproteins; atherosclerosis; baboons; biomarker; blood lipoprotein; blood lipoprotein metabolism; cardiovascular disorder risk; cholesterol; dietary constituent; dietary lipid; gene environment interaction; genetic polymorphism; genetic susceptibility; genotype; high density lipoproteins; linkage mapping; low density lipoprotein; nutrition related tag; oxidative stress; quantitative trait loci; tocopherols

Lipid and lipoprotein phenotypes and markers of oxidative damage are among the strongest, most consistent predictors of cardiovascular disease (CVD). With a few notable exceptions, the genes that govern variation in these important risk factor phenotypes are poorly characterized, and it appears that there may be many novel genes involved which were not previously suspected. The overarching goal of this project is to search the genome for quantitative trait loci (QTLs) that influence markers of lipoprotein metabolism and oxidative damage, to locate and identify these genes, and ultimately to better understand the metabolic processes involved. The traits that we will assess include lipid and lipoprotein measures of LDLs and HDLs and plasma indicators of oxidative damage. In addition, we will focus on identifying the effects ofgenotype x environment interactions on these CVD traits, specifically, responses to changing levels of dietary components, such as fat, cholesterol, and the antioxidant vitamin E, and also age-related changes. Exploiting our existing resources (i.e., pedigreed baboons, statistical genetic tools, frozen samples from previous diet studies, and availability of genotypes for the microsatellite markers comprising the baboon linkage map) plus data from a new dietary challenge experiment, we propose the following specific aims: (1) to detect, map, and statistically characterize QTLs that affect lipid and lipoprotein phenotypes on different diets, (2) to determine the extent to which genes affect indicators of oxidative damage, (3) to determine the pleiotropic effects of genes that influence lipoprotein phenotypes and oxidative damage indicators, (4) to determine the effects of genes on long-term longitudinal changes in CVD risk factors (by means of re-challenging baboons that had previously undergone the dual dietary challenge experiment), and (5) to determine the effects of genes on responses of oxidative damage indicators to a high dose of vitamin E (by means of adding a new diet to the re-challenge protocol). Accomplishing these specific aims will enable us to detect, locate, and characterize genes that govern variation in well established CVD risk factors. Based on the close phylogenetic relationship of baboons and humans, the results from our studies will provide insights into the genes that underlie the onset and progression of atherosclerosis in humans.

脂质和脂蛋白表型以及氧化损伤标志物是心血管疾病（CVD）最强、最一致的预测因子之一。除了少数值得注意的例外，控制这些重要风险因素表型变异的基因的特征很差，而且似乎可能涉及许多以前未被怀疑的新基因。本项目的总体目标是在基因组中寻找影响脂蛋白代谢和氧化损伤标记的数量性状位点（QTL）， 并识别这些基因，最终更好地了解所涉及的代谢过程。我们将评估的特征包括LDL和HDL的脂质和脂蛋白测量以及氧化损伤的血浆指标。此外，我们将重点确定基因型x环境相互作用对这些CVD性状的影响，特别是对饮食成分水平变化的反应，如脂肪，胆固醇和抗氧化剂维生素E，以及与年龄相关的变化。利用我们现有的资源（即，纯种狒狒，统计 遗传工具、来自先前饮食研究的冷冻样品以及组成狒狒连锁图的微卫星标记的基因型的可用性）加上来自新的饮食挑战实验的数据，我们提出以下具体目标：（1）检测、定位和统计学表征影响不同饮食的脂质和脂蛋白表型的QTL，（2）确定基因影响氧化损伤指标的程度，（3）确定影响脂蛋白表型和氧化损伤的基因的多效性效应 指标，（4）确定基因对CVD风险因素长期纵向变化的影响（通过重新挑战先前经历过双重饮食挑战实验的狒狒），以及（5）确定基因对氧化损伤指标对高剂量维生素E的反应的影响（通过在重新挑战方案中添加新的饮食）。实现这些特定目标将使我们能够检测，定位和表征控制已确立的CVD风险因素变异的基因。根据关闭 狒狒和人类的系统发育关系，我们的研究结果将提供对人类动脉粥样硬化发病和进展的基因的见解。