Metabolomics of World Trade Center-Lung Injury: Biomarker Validation, Longitudinal Assessment and Dietary Intervention

摘要 世贸中心建成后不久，代谢综合征（MetSyn）和血管疾病的生物标志物就出现了 (WTC) 颗粒物 (PM) 暴露可预测 WTC 肺损伤 (WTC-LI) 的发生。然而， WTC-PM 相关疾病的生物特征和分子决定因素尚未确定 全面表征并仍然是未开发的资源。而遗传和环境因素 是许多疾病过程的基础，代谢组学分析提供了与疾病表型的密切联系 并且深受微生物组的影响。 组合的多组学方法有可能成为 WTC-LI 早期诊断、预测的有效工具 疾病预后、治疗反应的监测标记以及疾病进一步发展的检测。 此外，通过技术支持的多学科营养减少 MetSyn 风险因素 干预还可以改善体重指数、肺功能和生活质量指标。 我们假设 WTC-LI 的多组学生物特征将有助于理解动态生物学 因环境影响而改变的途径，导致对 PM 暴露的异质反应 和治疗。我们将调查： 1. 多组学，包括与 WTC-LI 相关的表型组学、代谢物、微生物组和基因组图谱 在我们的试点症状 FIREHOUSE RCT 队列中。然后我们将使用系统生物学整合 MultiOME 优化疾病特定模型并确定 WTC-LI 的相关途径。 2. 使用纵向表型和数据的 FIREHOUSE 治疗模型的长期有效性 身体、心肺和心理健康的多学科评估。反馈将通过以下方式获得： 焦点小组和问卷调查。 3. 可行性和需求评估。这将是第一个针对 WTC 暴露受试者的多组学研究， 能够识别 WTC-LI 患者的独特模式，并激发特定的治疗 接近。这将使我们能够为 FIREHOUSE 模型的最终实施奠定基础。 我们将利用共同决策进行可行性和需求评估。验证我们的 其他人群的营养研究结果将证明其普遍性，并为其他世贸中心暴露人群提供帮助。 四年结束时的总体目标是了解我们量身定制的营养方案的长期影响 干预。这笔赠款产生的数据将增进对 WTC-LI 的了解并增强我们的能力 诊断和治疗 WTC 相关的气道损伤。合格的生物签名可以在其他方面进行外部验证 BMI 显着升高和 PM 暴露严重的人群也可能受益于该技术 - 支持饮食调整。从这项调查中汲取的经验教训可以在其他面临挑战的群体中得到验证 大量 PM 暴露导致重大公共卫生问题，以及哪些人可能受益于靶向治疗。

SUMMARY Biomarkers of metabolic syndrome(MetSyn) and vascular disease expressed soon after World Trade Center (WTC) particulate matter (PM) exposure predict development of WTC-Lung Injury (WTC-LI). However, the identification of biosignatures and molecular determinants of WTC-PM related disease are yet to be comprehensively characterized and remain as untapped resources. Whereas genetic and environmental factors are the foundation of many disease processes, metabolomic profiling provides a close link to disease phenotype and is profoundly influenced by the microbiome. A combined multiOMIC approach has the potential to be an effective tool for early diagnosis of WTC-LI, predictor of disease prognosis, surveillance marker of treatment response, and detection of further disease development. Furthermore, reducing MetSyn risk factors through a technology-supported multidisciplinary nutritional intervention can also improve BMI, lung function and quality of life measures. We hypothesize that multiOMIC biosignatures of WTC-LI will facilitate the understanding of the dynamic biologic pathways that are altered by environmental influences that lead to a heterogenous response to PM exposure and treatment. We will investigate the: 1. MULTIOMICS, including phenomics, metabolites, microbiome and genomic profiles associated with WTC-LI in our pilot symptomatic FIREHOUSE RCT cohort. We will then integrate the MultiOME using systems biology to optimize disease specific models and identify pertinent pathways of WTC-LI. 2. LONG-TERM EFFECTIVENESS of the FIREHOUSE treatment model using longitudinal phenotypic and multidisciplinary assessment of physical, cardiopulmonary, and mental health. Feedback will be obtained using focus groups and questionnaires. 3. FEASIBILITY AND NEED ASSESSMENT. This will be the first multiOMIC study in WTC-exposed subjects, enabling the identification of distinctive patterns in individuals with WTC-LI, and motivating specific therapeutic approaches. This will allow us to lay the ground work for the eventual implementation of the FIREHOUSE model. We will undertake a feasibility and need assessment using shared decision-making. VALIDATION of our nutritional findings in additional cohorts will prove its generalizability and assist other WTC exposed populations. The overall goal at the end of four years will be to understand the long-term effects of our tailored nutritional intervention. Data generated by this grant will improve the understanding of WTC-LI and enhance our ability to diagnose and treat WTC-related airway injury. Qualified bio-signatures can be externally validated in other cohorts that face significant elevations of BMI and heavy PM exposure who may also benefit from the technology- supported diet modification. Lessons learned from this investigation can be validated in other cohorts who face significant public health concerns due to heavy PM exposure, and who may benefit from targeted therapies.