The Roles of the Microbiome and Metabolome in Vascular Aging

 描述（由申请方提供）：拟定研究的总体目标是在博加卢萨心脏研究（BHS）的300名受试者中检查微生物组和代谢组在血管老化中的交叉作用。BHS是NIH资助的一项关于整个生命周期血管健康的纵向研究。目前的随访包括1，257名参与者，他们正在接受血管老化参数的仔细评估，包括动脉硬度，亚临床动脉粥样硬化，中心主动脉血压以及心脏结构和功能的无创测量。利用这些数据，我们将随机选择300名参与者进行微生物组测序和代谢组定量。这种采样策略将使我们能够有效和有力地检查微生物群和代谢物对血管衰老的多个参数的影响，包括以前没有探索过的关联。我们将使用下一代技术对BHS参与者粪便样本中的肠道微生物群落进行16 S rRNA测序。将利用生物信息学工具将生成的大量原始数据转化为最终产品，其中包含有关已确定分类群相对丰度的信息，以及微生物群α和β多样性的综合指标。将在多变量分析中检验个体和总体组成指标与血管老化参数的相关性。通过实施最先进的测序方法和复杂的分析技术，我们的研究将是第一个直接探索微生物群与血管衰老关系的研究。然后将使用结合LC-MS和GC-MS技术的创新方法进行非靶向代谢组学分析。将使用自动化管道将原始代谢组学数据处理为相对代谢物浓度的操作矩阵。将使用先进的多变量方法来检测单个代谢物和总体代谢组学特征与血管老化的相关性。由于我们将使用先前收集的血浆样本和表型数据，因此所提出的分析极具成本效益。为了更好地了解将微生物组与表型联系起来的生物学途径，我们将测试微生物群是否影响个体代谢物和代谢组学特征。这项分析将是第一个全面探索肠道微生物群与人类血浆代谢物库关系的分析，为影响心血管的生物学途径提供关键信息。 由于对CVD发展的生物学途径的重要机制性见解，拟议的研究可能有助于根据微生物群和代谢组学特征早期识别CVD高风险个体。基于这项工作，可以开发定制的策略来改变特定的血管衰老相关的微生物群和代谢物，有可能通过降低CVD发病率和死亡率来促进健康衰老和长寿。疾病（CVD）进展。

 DESCRIPTION (provided by applicant): The overall objective of the proposed study is to examine the intersecting roles of the microbiome and metabolome in vascular aging among 300 participants of the Bogalusa Heart Study (BHS). The BHS is an NIH-funded longitudinal study of vascular health across the lifespan. The current follow-up includes 1,257 participants who are undergoing careful assessment of vascular aging parameters, including non- invasive measures of arterial stiffness, subclinical atherosclerosis, central aortic blood pressure, and cardiac structure and function. Taking advantage of these data, we will randomly select 300 participants for microbiome sequencing and metabolome quantification. This sampling strategy will allow us to efficiently and powerfully examine the influence of microbiota and metabolites on multiple parameters of vascular aging, including associations which have not been explored previously. We will use next generation technology to conduct 16S rRNA sequencing of gut microbial communities from fecal samples of BHS participants. Bioinformatics tools will be utilized to transform the large amount of generated raw data to an end-product with information on the relative abundance of identified taxa, as well as composite metrics of microbiota alpha and beta diversity. Individual and overall compositional metrics will be tested for association with vascula aging parameters in multivariable analyses. Through the implementation of state-of-the-art sequencing methods and sophisticated analytic techniques, our research will be among the first to directly explore the relation of microbiota with vascular aging. Untargeted metabolomic profiling will then be conducted using innovative methodology that combines LC-MS and GC-MS technologies. An automated pipeline will be used to process raw metabolomics data into an operational matrix of relative metabolite concentrations. Advanced multivariable methods will be used to test associations of individual metabolites and overall metabolomic profile with vascular aging. Since we will use previously collected plasma samples and phenotype data, the proposed analysis is extremely cost-effective. To better understand the biological pathways linking microbiome to phenotype, we will test whether microbiota influence individual metabolites and metabolomic profiles. This analysis will be among the first to comprehensively explore the relation of gut microbiota to the human plasma metabolite repertoire, contributing critical information on the biological pathways influencing cardiovascular In addition to providing important mechanistic insights into the biological pathways underlying CVD development, the proposed research may aid in the early identification of individuals at high risk for CVD based on their microbiota and metabolomic profiles. Based on this work, tailored strategies may be developed to alter specific vascular aging related microbiota and metabolites, with the potential to promote healthy aging and longevity through the reduction of CVD morbidity and mortality. disease (CVD) progression.