Diet and Gene Effects on Atherosclerosis and CVD Risk

饮食和基因对动脉粥样硬化和心血管疾病风险的影响

• 批准号: 8376207
• 负责人: Michael Charles Mahaney
• 金额: $ 51.29万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376207
• 关键词: Acute; Address; Affect; Animal Feed; Animals; Antioxidants; Architecture; Arterial Fatty Streak; Arteries; Atherogenic Diet; Atherosclerosis; Autopsy; Bioinformatics; Biological; Biological Markers; Biopsy; Blood Vessels; Cardiovascular Diseases; Cardiovascular Pathology; Cell Count; Cell physiology; Cells; Cholesterol; Chronic; Clinical; Collaborations; Complex; Data; Data Analyses; Data Collection; Detection; Development; Diet; Dietary Cholesterol; Dietary Fats; Disease; Dissection; Endothelial Cells; Endothelium; Environment; Epidemiology; Exposure to; Family; Fat-Restricted Diet; Fatty acid glycerol esters; Functional disorder; Funding; Gene Components; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Genome; Genotype; Goals; Grant; Hand; Heart; Human; Human Resources; Individual; Inflammation; Injury; Intercellular adhesion molecule 1; Intrinsic factor; Lead; Lesion; Lipids; Lipoproteins; Literature; Liver; Lymphocyte; Measurement; Measures; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Profiling; Network-based; Oxidative Stress; Papio; Participant; Pathway interactions; Pattern; Phenotype; Physiology; Population; Predictive Value; Predisposition; Prevention; Primates; Process; Property; Quantitative Trait Loci; Reliance; Research; Research Activity; Research Personnel; Risk; Risk Factors; Science; Series; Severities; Sorting - Cell Movement; Stem cells; Structure; Supplementation; System; Systems Biology; Testing; Time; Tissues; Transcript; VWF gene; Variant; Vascular Cell Adhesion Molecule-1; Vascular Endothelium; Vasodilation; Vitamin E; Work; arterial lesion; base; cardiovascular disorder risk; clinical phenotype; complex biological systems; dietary supplements; feeding; genetic pedigree; human study; improved; in vivo; innovation; insight; intercellular cell adhesion molecule; nonhuman primate; novel; novel strategies; oxidative damage; programs; reconstruction; research study; response; tool; trait

The long-term goals of Project 2 are to understand the effects of diet and genes on variation in risk for cardiovascular disease (CVD). Our research to date has focused on localizing genes underlying variation in lipids, lipoproteins, oxidative stress and inflammation, which are among the strongest, most consistent predictors of CVD in the epidemiological literature. However, many of these detected genes act in concert to influence complex biological systems. Our central hypothesis is that there are pleiotropic networks of coordinately-regulated genes and clinical risk factor phenotypes that influence susceptibility to CVD. We propose to apply a systems biology-based approach to address this hypothesis. In Aim 1, we will construct pleiotropic networks of genes underlying correlated responses of lipoproteins and related CVD risk factors to dietary cholesterol, fat, and anti-oxidant supplementation. Utilizing data from completed dietary challenge experiments and from whole-genome transcriptional profiles for 500 baboons, we will construct networks of clinical phenotypes and expression profiles, and compare these networks to evaluate the relationships between expression and risk factor variation. In a newly added sub-aim, we will validate these results by analyzing transcriptional profile data and phenotype measures already in hand from a large-scale study of the genetics of CVD risk factors in extended human families. In Aim 2, we will construct pleiotropic networks of genes underlying co-variation in functional markers of the vascular endothelium. Phenotypes include endothelial progenitor cell numbers, ex vivo primary endothelial cell (EC) properties plus in vivo functional indicators of the vascular endothelium, including vascular reactivity and circulating levels of VCAM, ICAM, and vWF. We also will determine transcriptional profiles from primary ECs in order to directly compare networks of expression and risk factor phenotypes. In Aim 3 we will evaluate contributions of risk factors and biological network components identified in Aims 1 and 2 to variation in extent of lesions following a chronic, 2-year diet challenge. Data for this aim include measures related to lipoprotein metabolism and oxidative damage, assessments of endothelial function, and EC transcriptional profiles. Additionally, as part of this aim, we also will assess the effects of acute exposure (7-weeks) to the atherogenic diet on EC gene expression and, if such effects are detected, we will test for their relationships to later lesion formation and to gene expression in another critical tissue or CVD, the liver. Completion of these aims will provide valuable insights into the interrelationships between known and novel CVD risk factors in general; identify networks of genes whose expression is affected by dietary fat; validate these networks and their components in humans; and examine the relationships between dietary fat, EC gene expression, and arterial lesion formation.

项目2的长期目标是了解饮食和基因对糖尿病风险变化的影响。 心血管疾病（CVD）。迄今为止，我们的研究主要集中在定位基因的变异， 脂质，脂蛋白，氧化应激和炎症，这是最强的，最一致的， 流行病学文献中CVD的预测因子。然而，这些检测到的基因中有许多是一致行动的， 影响复杂的生物系统。我们的中心假设是，有一个多效性网络， 协同调节的基因和临床危险因素表型影响CVD的易感性。我们 建议应用基于系统生物学的方法来解决这一假设。在目标1中，我们将构建 脂蛋白和相关CVD危险因子对脂蛋白的相关反应的基因多效性网络 膳食胆固醇、脂肪和抗氧化剂补充剂。利用来自已完成饮食挑战的数据 实验和500只狒狒的全基因组转录谱，我们将构建 临床表型和表达谱，并比较这些网络，以评估关系 表达和风险因子变异之间的关系。在新增加的子目标中，我们将通过以下方式验证这些结果： 分析转录谱数据和表型措施已经在手，从一个大规模的研究， 大家庭中CVD危险因素的遗传学。在目标2中，我们将构建多效性网络 血管内皮功能标志物中潜在的共变异基因。表型包括 内皮祖细胞数量、离体原代内皮细胞（EC）特性加上体内功能 血管内皮的指标，包括血管反应性和VCAM，ICAM， 和vWF。我们还将确定原代EC的转录谱，以便直接比较 表达和风险因子表型的网络。在目标3中，我们将评估风险因素的贡献， 目的1和2中鉴定的生物网络成分与慢性， 2-年的饮食挑战。用于该目的的数据包括与脂蛋白代谢和氧化代谢相关的测量。 损伤、内皮功能评估和EC转录谱。此外，作为这一 目的是评估急性暴露（7周）致动脉粥样硬化饮食对EC基因的影响。 表达，如果检测到这种影响，我们将测试它们与后期病变形成的关系， 基因在另一个关键组织或CVD，肝脏中的表达。这些目标的实现，将为 深入了解已知和新的CVD风险因素之间的相互关系;识别 其表达受膳食脂肪影响的基因;在人类中验证这些网络及其组件; 并研究膳食脂肪、EC基因表达和动脉病变形成之间的关系。