Protein Adducts as Measures of Exposure Throughout Childhood Development

蛋白质加合物作为整个儿童发育过程中暴露量的衡量标准

基本信息

批准号：
9332404
负责人：
William E Funk
金额：
$ 19.75万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332404
关键词：
21 year old Address Age Binding Sites Biological Assay Biological Markers Biology Birth Blood Blood Volume Blood specimen Carcinogens Chemical Exposure Chemicals Child Child health care Childhood Chronic Disease Collaborations Collection Complement Conceptions Data Detection Development Diet Disease Dose Drops Environment Environmental Exposure Environmental Hazards Environmental Health Environmental Pollutants Equipment and supply inventories Etiology Exposure to Fetus Fingers Foundations Future Genes Goals Growth and Development function Health Heel Human Human Genome Individual Infant Inflammation Knowledge Laboratories Letters Libraries Life Link Logistics Longevity Malignant Neoplasms Maps Mass Spectrum Analysis Measures Methods Molecular Profiling National Institute of Environmental Health Sciences Newborn Infant Oxidative Stress Paper Peptides Plasma Poison Population Research Predisposition Proteins Resolution Risk Assessment Risk Factors Sample Size Sampling Serum Albumin Source Spottings Strategic Planning Time Work adduct base biomarker discovery candidate marker critical period disability early childhood epidemiology study experimental study exposed human population fetal genome wide association study in vivo minimally invasive nano new technology novel postnatal protein E public health relevance residence tool

项目摘要

DESCRIPTION (provided by applicant): Periods of fetal, infant, and early childhood development are remarkably venerable to environmental hazards, and exposures to toxic chemicals during these critical windows of susceptibility have been linked with disease, disabilities, and adverse health in childhood and across the entire life span. Consequently, the timing of exposure during early-life is a critical factor to consider when investigating environmental causes of disease. As a complement to the human genome, the concept of the exposome - representing the totality of human exposures occurring from conception onward - has become increasingly salient in the field of environmental health sciences for investigating disease etiologies. While it is currently not possible to measure all chemicals in blood samples using single experiments (analogous to gene-wide association studies for measuring genes), important classes of chemicals can be investigated during critical period of development. One important class of chemicals is electrophiles, which are highly reactive compounds that have been linked to a vast majority of cancers and chronic diseases. Electrophiles have both exogenous (e.g., environmental pollutants and diet) and endogenous (e.g., oxidative stress and inflammation) sources, and thus reflect a broad spectrum of important molecules ranging across the entire exposure-disease continuum. However, because electrophiles tend to have very short life spans in vivo, they normally cannot be measured directly in blood samples. This has motivated the use of protein addition products (adducts) as biomarkers for estimating exposures to reactive electrophilic chemicals, which reflect an integration of exposure to short-lived electrophiles over the residence time of the protein (e.g., weeks to months). In this proposal we will apply a two-stage approach that directly aligns with the NIEHS 2012-2017 Strategic Plan. First, we will apply a new omics strategy called adductomics to map the early-life exposome from before birth onward to age 21. Using data from these experiments, as well as data collected from collaborating laboratories, we will then crate a library of all detectable HSA-Cys34 adducts. Finally, we will develop and validate a high-throughput muiltiplexed assay for quantifying panels of targeted adducts in dried blood samples - drops of blood collected on filter paper using a simple and minimally-invasive heel or finger prick. Given the overwhelming lack of human in vivo data on early-life environmental exposures and their impacts on children's health, this proposal offers a unique opportunity to bridge this critical gap in scientific knowledge. The biomarker approaches developed in this proposal will provide the first maps of the early-life adductome, and will provide specific tools for investigating environmental causes of diseases and disorders in future studies.

描述（由适用提供）：胎儿，婴儿和幼儿发育的时期对环境危害非常崇高，并且在这些易感性的这些关键易感性窗口中对有毒化学物质的暴露与疾病，疾病和童年和整个生命周期的不良健康有关。因此，在研究疾病的环境原因时，要考虑的关键因素是考虑的关键因素。作为对人类基因组的补充，暴露的概念 - 代表从概念开始的人类暴露的总体暴露 - 在调查疾病病因学领域的环境健康科学领域变得越来越重要。虽然目前无法使用单个实验（类似于基因的基因研究）测量血液样本中的所有化学物质），但在关键的发育期间，可以研究重要的化学物质类别。一类重要的化学物质是电生物，它们是与绝大多数癌症和慢性疾病有关的高反应性化合物。亲电器具有极端（例如，环境污染物和饮食）和内源性（例如氧化应激和炎症）来源，因此反映了整个暴露疾病连续体的重要分子的广泛范围。但是，由于电泳往往在体内寿命很短，因此通常无法直接在血液样本中测量它们。这融合了使用蛋白质添加产物（加合物）作为估计反应性亲电化学物质暴露的生物标志物，这反映了在蛋白质的停留时间（例如，几周到几个月）中暴露于短寿命的电力物的整合。在此提案中，我们将采用两阶段的方法，该方法与NIEHS 2012-2017的战略计划直接相吻合。首先，我们将采用一种称为辅助组学的新的OMIC策略来绘制从出生开始到21岁之前的早期寿命暴露体。使用这些实验的数据以及从协作实验室收集的数据，然后我们将为所有可检测的HSA-CYS34库铺一个库加合物。最后，我们将开发并验证高通量的静止测定法，以量化干血样品中靶向加合物的面板 - 使用简单而微不足道的高跟鞋或指尖在滤纸上收集的血液滴。鉴于人类在体内缺乏关于早期生活环境暴露及其对儿童健康的影响的缺乏人类的数据，该提案为弥合科学知识的这一关键差距提供了独特的机会。本提案中开发的生物标志物方法将提供早期增长的第一张地图，并将提供特定的工具来研究未来研究中疾病和疾病的环境原因。