DIET AND GENE EFFECTS ON THEROSCLEROSIS AND CVD RISK

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级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。到目前为止，我们的研究主要集中在定位血脂、脂蛋白、氧化应激和炎症的潜在基因，在流行病学文献中，这些都是心血管疾病最强烈、最一致的预测因素。然而，许多这些检测到的基因协同作用，影响复杂的生物系统。我们的中心假设是，存在影响心血管疾病易感性的协调调节基因和临床危险因素表型的多效性网络。我们建议应用一种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心血管疾病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多效性基因网络。利用完成的饮食挑战实验和500只狒狒的全基因组转录图谱的数据，我们将构建临床表型和表达图谱的网络，并对这些网络进行比较，以评估表达和危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图谱数据和已有的表型测量来验证这些结果，这些数据和表型测量来自对人类大家庭中心血管疾病危险因素遗传学的大规模研究。在目标2中，我们将构建与血管内皮功能标记物的共同变异相关的基因的多效性网络。表型包括内皮祖细胞数量、体外原代内皮细胞(EC)特性以及体内血管内皮细胞功能指标，包括循环中VCAM、ICAM和vWF的水平。我们还将确定原代内皮细胞的转录图谱，以便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和目标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与脂蛋白代谢和氧化损伤相关的测量，内皮功能的评估，以及EC转录图谱。此外，作为这一目标的一部分，我们还将评估急性暴露于致动脉粥样硬化的饮食(7周)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来的病变形成和另一关键组织或CVD-肝脏的基因表达的关系。这些目标的完成将对已知和新的心血管疾病危险因素之间的相互关系提供有价值的见解；识别其表达受饮食脂肪影响的基因网络；验证这些网络及其在人类中的成分；并检查饮食脂肪、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.