Pre-disease biomarkers of persistent organic pollutants, immune system, and amyotrophic lateral sclerosis

持久性有机污染物、免疫系统和肌萎缩侧索硬化症的病前生物标志物

• 批准号: 10252748
• 负责人: Marc G Weisskopf
• 金额: $ 50万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2023-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252748
• 关键词: Pre; disease; biomarkers; persistent; organic

Project Summary/Abstract We propose to study the relation between blood concentrations of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) incidence and survival using blood samples collected well before the onset of ALS. We will also explore whether those exposures, and ALS, are associated with changes in extracellular vesicles (EV) derived specifically from immune system cells to identify mechanisms related to the exposures, ALS, and associations between them. We will conduct a case-control study nested within large prospective cohort studies in Denmark and Finland that total almost 120,000 participants. The participants provided blood samples at the cohort baselines, and we identify ALS cases during follow-up via linkage with National registries. We anticipate a total of 265 ALS cases that occurred after cohort enrollment. We will randomly select 2 controls per case individually matched on age, sex, and cohort from among all non-ALS cases alive at the time the case is diagnosed. Extensive questionnaire data from the cohorts is available for regression model adjustments. The blood samples will be analyzed for organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). EVs will be isolated and characterized in terms of size and number, and percentage expressing specific surface markers that identify EVs derived from cells of the immune system. By nesting this study within large Danish and Finnish prospective cohort studies that have blood samples from many years before ALS, we have a unique setting that will allow us for the first time to assess the relation between toxicant exposures and ALS using individual biomarkers of exposure from samples collected before ALS onset, thereby avoiding problems associated with questionnaire recall of past exposures or biomarker measurements in samples collected after ALS onset that may be affected by disease (leading to possible reverse causation). The pre-disease biosamples also allow us to explore biological mechanisms that may underlie the associations we see and possibly identify biomarkers of future disease risk and survival, thereby providing insight into ALS pathophysiology.

项目概要/摘要 我们建议研究持久性有机污染物（POP）的血液浓度之间的关系 以及肌萎缩侧索硬化症 (ALS) 的发病率和生存率，使用在治疗前收集的血液样本 ALS 发作。我们还将探讨这些暴露和 ALS 是否与 专门源自免疫系统细胞的细胞外囊泡（EV），用于识别与免疫系统相关的机制 暴露、ALS 以及它们之间的关联。我们将进行一项大型病例对照研究 丹麦和芬兰的前瞻性队列研究共有近 120,000 名参与者。参加者 提供了队列基线的血液样本，我们在随访期间通过与 国家登记处。我们预计队列入组后总共会发生 265 例 ALS 病例。我们将 每个病例从所有非 ALS 中随机选择 2 个在年龄、性别和队列上分别匹配的对照 确诊时病例还活着。来自队列的大量问卷数据可用于 回归模型调整。血液样本将进行有机氯农药分析， 多氯联苯 (PCB) 和多溴二苯醚 (PBDE)。电动汽车将被隔离 以大小和数量以及表达特定表面标记的百分比来表征 EV 源自免疫系统细胞。通过将这项研究嵌套在大型丹麦语和芬兰语中 前瞻性队列研究拥有 ALS 发生前多年的血液样本，我们拥有独特的环境 这将使我们能够首次使用个体评估有毒物质暴露与 ALS 之间的关系 从 ALS 发病前收集的样本中获取暴露的生物标志物，从而避免与 问卷调查回顾 ALS 发病后收集的样本中过去的暴露或生物标志物测量结果 可能受到疾病的影响（导致可能的反向因果关系）。病前生物样本还使我们能够 探索可能构成我们所看到的关联并可能识别生物标志物的生物机制 未来疾病风险和生存率，从而提供对 ALS 病理生理学的深入了解。