Functional Cardio-Metabolomics

描述（由申请方提供）：心血管疾病（CVD）是发病率和死亡率的主要来源。尽管进行了最大限度的治疗干预，但仍存在重大风险。迫切需要发现与CVD发病机制相关的途径。拟议的研究将联合收割机无偏代谢组学方法与更多的定量靶向分析、机制动物模型和人体研究相结合，以定义与CVD发病机制相关的新分析物和途径。在目标1中，我们提出了在动物疾病模型和人类中进行新的机制研究，重点是在我们最初的无偏见代谢组学研究期间最近发现的一种新的未发表的途径。我们在小鼠模型和人类临床研究中积累了大量的初步数据，显示红肉中丰富的膳食营养素通过肠道植物群代谢，并与动脉粥样硬化有关。未发表的靶向代谢组学研究、无菌小鼠和人类抗生素抑制的同位素示踪研究以及其他机制动物模型研究共同表明，肠道植物群产生的至少三种不同代谢物可能具有影响动脉粥样硬化易感性和胆固醇代谢的直接生物活性。在目标2中，我们建议使用两个不同的和明确定义的临床队列，大大扩展我们最初的无偏倚代谢组学研究。在接受择期心脏评估和长期随访的受试者中进行的研究将使我们能够发现与动脉粥样硬化性心脏病及其不良并发症心脏病发作、心力衰竭和死亡相关的新分析物和途径。而另一项代谢组学研究，即通过连续冠状动脉血管内超声[IVUS]监测的临床试验，将使我们能够定义与对高效他汀类药物治疗反应相关的分析物和途径。成功完成我们提出的研究计划将为开发新的诊断测试和治疗方法提供机会，用于治疗和预防动脉粥样硬化性心脏病及其主要并发症。它还将进一步建立红肉中丰富营养素的肠道菌群依赖性代谢，作为通过无偏代谢组学发现的心血管疾病发病机制的新途径。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) represents the major source of morbidity and mortality. Despite maximal therapeutic intervention, significant risks remain. There is a critical need for discovery of pathways linked to CVD pathogenesis. The proposed studies combine unbiased metabolomics approaches, with more quantitative targeted analyses, and mechanistic animal models and human studies, to define novel analytes and pathways linked to CVD pathogenesis. In aim 1, we propose new mechanistic studies in animal models of disease, and in humans, centered around a new and unpublished pathway discovered recently during performance of our initial unbiased metabolomics studies. We have accrued substantial preliminary data in both mouse models and human clinical investigations showing a dietary nutrient abundant in red meat is metabolized by gut flora and is linked to atherosclerosis. Unpublished targeted metabolomics studies, isotope tracer studies in germ free mice and humans ¿ antibiotic suppression, and additional mechanistic animal model studies, collectively indicate at least three distinct metabolites produced by gut flora may possess direct biological activity impacting upon atherosclerosis susceptibility and cholesterol metabolism. In aim 2 we propose to substantially extend upon our initial unbiased metabolomics investigations using two distinct and well defined clinical cohorts. Studies in subjects undergoing elective cardiac evaluations and for whom long term follow-up is available will enable us to discover new analytes and pathways associated with development of atherosclerotic heart disease and its adverse complications heart attack, heart failure and death. While metabolomics studies in another, a clinical trial monitored by sequential coronary intravascular ultrasound [IVUS]), will allow us to define analytes and pathways associated with response to therapy for high potency statins. Successful completion of our proposed research program will provide opportunities for development of both novel diagnostic tests and therapeutic approaches for the treatment and prevention of atherosclerotic heart disease and its major complications. It will also further establish gut flora-dependent metabolism of an abundant nutrient in red meat as a new pathway for cardiovascular disease pathogenesis discovered through unbiased metabolomics.