Metabolomics of subclinical and clinical cardiovascular disease

描述（申请人提供）：心血管疾病（CVD）是一个复杂的过程，涉及饮食、环境和健康行为的遗传、表观遗传和生活史变化。我们已经组建了一个由内科科学家、实验心脏病学家、生理生物化学家和计算生物学家组成的综合团队来解决这个问题。我们将应用一个新的高分辨率代谢平台，广泛表型亚临床和临床诊断CVD队列，以发现新的代谢危险因素。代谢组学平台测量人体血浆中的7000种化学物质，包括大多数已知生化途径中的化学物质。正在进行的预测性健康队列已经广泛地对亚临床血管疾病（内皮功能障碍、颈动脉内膜-中膜厚度、动脉僵硬和微血管功能障碍）和各种氧化应激和炎症的生物标志物进行表型分析。正在进行的CVD队列具有临床CVD（通过血管造影时是否存在冠状动脉疾病及其严重程度以及既往心肌梗死史来测量），并将在整个项目中进行临床随访。生物信息学工具将用于开发代谢危险因素的功能代谢和遗传图谱。这些功能图谱将指导CVD小鼠模型的机制研究（部分颈动脉结扎和apoE-/-），采用新的化学和蛋白质传递工具来测试CVD发展中的代谢物和紊乱的代谢途径。发现的代谢、遗传和途径谱将与现有知识一起用于开发新的血管疾病风险模型，该模型将在独立队列中进行验证，数据包括亚临床血管疾病的4年进展，CVD患者发生不良心血管事件，以及外周动脉疾病患者的不良心血管事件随访。这些相互作用的成分将创建一个系统，根据代谢模式和预测模型对心血管疾病风险表型进行分类，这些模型整合了代谢模式、途径和功能网络。长期目标是一种可负担得起的方法，可用于预测疾病易感性、诊断、风险分层、治疗反应和预后。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is a complex process involving genetic, epigenetic and life history variations in diet, environment and health behaviors. We have assembled an integrated team of physician scientists, experimental cardiologists, physiological biochemists and computational biologists to address this problem. We will apply a new high-resolution metabolic platform to extensively phenotyped subclinical and clinically diagnosed CVD cohorts to discover new metabolic risk factors. The metabolomics platform measures 7000 chemicals in human plasma, including chemicals in most known biochemical pathways. The ongoing predictive health cohort has been extensively phenotyped for subclinical vascular disease (endothelial dysfunction, carotid intima-media thickness, arterial stiffness, and microvascular dysfunction) and a wide variety of biomarkers of oxidative stress and inflammation. The ongoing CVD cohort has clinical CVD (measured as presence/absence of coronary artery disease at angiography and its severity, and previous history of myocardial infarction), and will be followed clinically throughout this project. Bioinformatic tools will be ued to develop functional metabolic and genetic maps of the metabolic risk factors. These functional maps will guide mechanistic studies in mouse models of CVD (partial carotid ligation and apoE-/-) employing novel chemical and protein delivery tools to test the metabolites and perturbed metabolic pathways in CVD development. The discovered metabolic, genetic and pathway profiles will be used with existing knowledge to develop a new vascular disease risk model, which will be validated in independent cohorts with data on 4-year progression of subclinical vascular disease, patients with CVD developing adverse cardiovascular events, and patients with peripheral artery disease being followed for adverse CVD events. The interacting components will create a system to classify CVD risk phenotype in terms of metabolic patterns and predictive models that integrate the metabolic patterns, pathways, and functional networks. The long-term goal is an affordable approach that can be used for predicting disease susceptibility, diagnosis, risk stratification, response to therapy and prognosis.