DIET AND GENE EFFECTS ON THEROSCLEROSIS AND CVD RISK

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 项目2的长期目标是了解饮食和基因对心血管疾病（CVD）风险变化的影响。 迄今为止，我们的研究主要集中在定位脂质，脂蛋白，氧化应激和炎症变化的潜在基因，这些基因是流行病学文献中最强，最一致的CVD预测因子之一。 然而，这些检测到的基因中有许多共同影响复杂的生物系统。我们的中心假设是，有协调调节基因和临床危险因素表型的多效性网络，影响CVD的易感性。 我们建议应用系统生物学为基础的方法来解决这个假设。 在目标1中，我们将构建脂蛋白和相关CVD危险因素对膳食胆固醇、脂肪和抗氧化剂补充的相关反应的基因多效性网络。利用已完成的饮食挑战实验和500只狒狒的全基因组转录谱数据，我们将构建临床表型和表达谱网络，并比较这些网络，以评估表达和风险因素变异之间的关系。在一个新增加的子目标中，我们将通过分析转录谱数据和表型措施来验证这些结果，这些数据和表型措施已经从大规模研究人类大家庭中CVD危险因素的遗传学中获得。在目标2中，我们将构建血管内皮功能标志物共变异基因的多效性网络。 表型包括内皮祖细胞数量、离体原代内皮细胞（EC）特性以及血管内皮的体内功能指标，包括VCAM、ICAM和vWF的循环水平。 我们还将确定原代内皮细胞的转录谱，以直接比较表达网络和风险因子表型。在目标3中，我们将评估目标1和2中确定的风险因素和生物网络成分对慢性2年饮食挑战后病变程度变化的贡献。这一目标的数据包括脂蛋白代谢和氧化损伤相关的措施，内皮功能的评估，和EC转录谱。 此外，作为这一目标的一部分，我们还将评估急性暴露（7周）致动脉粥样硬化饮食对EC基因表达的影响，如果检测到这种影响，我们将测试它们与后期病变形成和另一个关键组织或CVD（肝脏）中基因表达的关系。这些目标的完成将为已知和新的CVD风险因素之间的相互关系提供有价值的见解;识别其表达受膳食脂肪影响的基因网络;验证这些网络及其在人体中的组成部分;并检查膳食脂肪，EC基因表达和动脉病变形成之间的关系。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. DESCRIPTION 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 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.