Mapping the Plasma Exposome and its Association with Human Cardiovascular Disease

绘制血浆暴露体图谱及其与人类心血管疾病的关系

• 批准号: 9233700
• 负责人: Mohit Jain
• 金额: $ 57.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9233700
• 关键词: Accounting; Adult; Age; Award; Bees; Biological; Biological Assay; Biological Markers; Biology; Blood; Blood Circulation; Blood specimen; Cardiovascular Diseases; Cardiovascular system; Characteristics; Chemicals; Clinical; Computational Science; Conceptions; Coupling; Data; Databases; Development; Diet; Disease; Environmental Epidemiology; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiology; Ethnic Origin; Foundations; Gender; Genes; Genetic; Genetic Predisposition to Disease; Goals; Health; Heart; Heart Diseases; Heavy Metals; Human; Individual; Infectious Agent; Liquid Chromatography; Longevity; Maps; Mass Spectrum Analysis; Measures; Methods; Molecular; Monitor; National Institute of Environmental Health Sciences; Natural Product Drug; Nature; Nested Case-Control Study; Onset of illness; Outcome; Participant; Particulate Matter; Patients; Pharmaceutical Preparations; Physiology; Plasma; Pollution; Population; Population Attributable Risks; Recording of previous events; Research; Research Design; Research Personnel; Role; Sampling; Scanning; Scientist; Surrogate Markers; Technology; Time; Tobacco; Variant; aerosolized; analytical tool; base; cardiogenesis; cardiovascular disorder risk; case control; cohort; demographics; design; disorder risk; ethnic diversity; genetic variant; human disease; human morbidity; human mortality; innovation; insight; liquid chromatography mass spectrometry; meetings; microbiota; mortality; novel; novel strategies; pollutant; programs; prospective; small molecule; toxicant

PROJECT SUMMARY Human physiology and disease pathobiology are a manifestation of underlying genetic predisposition interacting with superimposed environmental exposures. Whereas genetic factors are generally stable from conception, environmental exposures are dynamic over the lifespan, and ultimately account for up to 90% of population-attributable risk for human disease, including for cardiovascular disease, the number cause of mortality in the developed world. The totality of environmental exposures, or the ‘exposome’, represents the aggregate of both internal exposures originating from host state/physiology and host microbiota, as well as external exposures deriving from toxicants and chemicals, aerosolized particulate matter and pollution, infectious agents, as well as diet and drugs. These environmental exposures result in the introduction of small molecules into human circulation where they may be monitored as biomarker surrogates of specific exposures even years or decades prior to onset of overt disease. To date, targeted approaches have begun to detail the small molecules that comprise the plasma exposome in humans. Still lacking, however, is a global view of the thousands of known and yet undiscovered small molecules that comprise the human exposome on a population level scale and rigorous association of these small molecules with the prospective development of human disease. The fundamental barrier in our understanding of the exposome and its role in human disease remains the lack of advanced analytical approaches that enable the simultaneous and rapid measure of the thousands of small molecules that comprise the plasma exposome on a population level scale. In this NIEHS Outstanding New Environmental Scientist (ONES) Award, it is our central goal to comprehensively map the human plasma exposome, understand its dynamic nature over time, and determine its role in human cardiovascular disease. To do so, we will apply novel, high throughput mass spectrometry based approaches to measure the thousands of environmentally derived small molecules present in human plasma. In serial plasma samples obtained over time from 1000 healthy individuals we will determine the natural variation in the exposome from individual to individual and over time in a single individual, the components of the exposome attributable to specific environmental exposures, and the relationship between the exposome and over forty baseline clinical demographics. Additionally, in two independent, large scale prospective epidemiological cohorts, we will determine the association between specific exposome related small molecules, interaction with disease associated genetic variants, and the prospective development of cardiovascular disease years in advance. This NIEHS ONES award will provide support for a uniquely poised Early State Investigator with diverse expertise in mass spectrometry based analytics, environmental epidemiology, computational sciences, cardiovascular biomedicine and a history of high impact biological discovery, as well as provide a foundation from which to launch an innovative, long-term research program committed to the study of environmental health sciences. !

项目概要 人类生理学和疾病病理学是潜在遗传倾向的表现 与叠加的环境暴露相互作用。 在受孕期间，环境暴露在整个生命周期中是动态的，最终占 90% 人口归因的人类疾病风险，包括心血管疾病， 发达国家的死亡率是指环境暴露总量或“暴露组”。 来自宿主状态/生理和宿主微生物群的内部暴露的总和，以及 来自有毒物质和化学品、雾化颗粒物和污染的外部暴露， 传染源以及饮食和药物这些环境暴露会导致少量的引入。 分子进入人体循环，可以作为特定暴露的生物标志物替代物进行监测 甚至在明显疾病发生前的几年或几十年内，迄今为止，有针对性的方法已经开始详细说明。 然而，仍然缺乏对构成人类血浆暴露组的小分子的整体认识。 数以千计的已知但尚未发现的小分子组成了人类暴露组 人口水平规模以及这些小分子与未来发展的严格关联 我们理解暴露组及其在人类疾病中的作用的根本障碍。 疾病仍然缺乏能够同时快速测量的先进分析方法 在群体水平上构成血浆暴露组的数千个小分子。 NIEHS杰出新环境科学家（ONES）奖，我们的中心目标是全面 绘制人体血浆暴露组图，了解其随时间的动态性质，并确定其在人体中的作用 为此，我们将应用基于新型高通量质谱的方法。 连续测量人体血浆中存在的数千种环境衍生的小分子。 随着时间的推移从 1000 名健康个体中获取血浆样本，我们将确定血浆样本的自然变异 从个体到个体的暴露组，以及随着时间的推移在单个个体中，暴露组的组成部分 归因于特定的环境暴露，以及暴露组与超过四十之间的关系 此外，在两个独立的、大规模的前瞻性流行病学研究中。 队列中，我们将确定特定暴露组相关小分子之间的关联、与 疾病相关的遗传变异，以及心血管疾病的未来发展 该 NIEHS ONES 奖项将为具有独特能力的早期状态调查员提供支持。 基于质谱分析、环境流行病学、计算科学、 心血管生物医学和高影响力生物发现的历史，并提供基础 由此启动一项创新的、长期的研究计划，致力于环境问题的研究 健康科学。 ！