Linking long-term air pollution exposure with inflammation, ALS risk, and disease progression

摘要 空气污染是肌萎缩侧索硬化症（ALS）的一个未充分研究的危险因素。ALS和空气污染导致- 炎症，但没有研究将这两个关键的ALS主题联系起来。长期目标是预防、减缓或停止 ALS进展。总体目标是确定长期空气污染暴露如何改变ALS风险， 进展和生存，并深入了解炎症在神经元损伤途径中的作用。的 中心假设是空气污染触发了外周免疫谱，这是一种重要的病理生理学， ALS风险、进展和生存的逻辑因素。根据初步数据显示，i）ALS病例 与对照组相比，颗粒物（PM）2.5暴露量较高，ii）PM2.5暴露量最高的病例 增加了嗜酸性粒细胞、自然杀伤细胞标志物和细胞因子活化，以及iii）现有文献连接- 将空气污染暴露与ALS疾病严重程度联系起来，其基本原理是将空气污染与ALS炎症联系起来， 简介将加强ALS和空气污染之间的联系，以告知关键和必要的预防措施。 战略，以及定义新的疾病生物标志物和治疗靶点。核心假设是 通过追求两个具体目标进行测试：1）描述病例和对照组的空气污染暴露特征， 密歇根大学ALS患者生物储存库，并确定这些暴露如何与ALS风险相关， 和生存;和2）评估免疫概况作为空气污染之间的关联介质- 暴露与ALS风险、进展和生存率的关系，使用的数据来自于美国密歇根大学的病例和对照组。 密歇根州ALS患者生物储存库。在目标1a中，对病例和对照组的空气污染暴露进行了估计 使用成熟的预测模型，预测主要环境空气污染物，包括PM2.5、NO2和交通相关污染物。 空气污染物（TRAPs）。风险敞口将跨越2000年至2020年，并占住宅他- 所有受试者的病史和ALS病例的症状发作日期。目标1b将研究这些暴露如何与 与ALS风险相关，在Aim 1c中，与ALS进展和生存相关。目标2a将确定免疫亲- 与目标1中开发的长期、时空、空气污染暴露相关的文件。由于文献 将空气污染与炎症联系起来，而炎症与ALS的进展和生存有关，Aim 2b将 通过进行调解分析，调查免疫概况是否在因果途径中发挥作用， 空气污染与ALS风险，进展和生存之间的关系。本申请中提出的研究是创新的。 在申请人看来，这是有意义的，因为它严格地开发了彻底的时空空气污染数据， 捕捉时间和空间的空气污染趋势，并分析了深表型ALS和对照队列 来自工业发达的中西部。拟议的研究是重要的，因为它将提供关键的数据，对疾病， 与ALS风险、进展和免疫途径相关的空气污染、免疫特征和免疫途径， 生存最后，由于空气污染是一个可改变的风险因素，从这一建议的知识可以指导预防- 治疗效果、治疗靶点和用于临床研究的基于血液的生物标志物。

ABSTRACT Air pollution is an understudied amyotrophic lateral sclerosis (ALS) risk factor. ALS and air pollution cause in- flammation, yet no studies link these two critical ALS topics. The long-term goals are to prevent, slow, or stop ALS progression. The overall objective is to determine how long-term air pollution exposure alters ALS risk, progression, and survival and gain insight into the role of inflammation on the path to neuronal damage. The central hypothesis is that air pollution triggers peripheral immune profiles that are an important pathophysio- logic agent of ALS risk, progression and survival. Guided by preliminary data showing that i) ALS cases have higher particulate matter (PM)2.5 exposure compared to controls, ii) the cases with the highest PM2.5 exposures have increased eosinophils, natural kill cell markers, and cytokine activation, and iii) existing literature connect- ing air pollution exposure to ALS disease severity, the rationale is that linking air pollution to ALS inflammatory profiles will strengthen the association between ALS and air pollution to inform critical and needed preventative strategies, as well as define new disease biomarkers and therapeutic targets. The central hypothesis will be tested by pursuing two specific aims: 1) Characterize air pollution exposures for cases and controls in the Uni- versity of Michigan ALS patient biorepository and determine how these exposures associate with ALS risk, pro- gression, and survival; and 2) Evaluate immune profiles as a mediators of the associations between air pollu- tion exposures and ALS risk, progression, and survival using data from cases and controls in the University of Michigan ALS patient biorepository. In Aim 1a, air pollution exposures for cases and controls are estimated using well-established prediction models for key ambient air pollutants including PM2.5, NO2, and traffic related air pollutants (TRAPs). Exposures will span the years 2000 through 2020 and account for the residential his- tory for all subjects and symptom onset date for ALS cases. Aim 1b will investigate how these exposures asso- ciate with ALS risk and, in Aim 1c, with ALS progression and survival. Aim 2a will determine the immune pro- files that associate with long-term, spatiotemporal, air pollution exposures developed in Aim 1. As the literature links air pollution to inflammation and inflammation is linked to ALS progression and survival, Aim 2b, will in- vestigate whether immune profiles play a role in the causal pathway by performing a mediation analysis be- tween air pollution and ALS risk, progression, and survival. The research proposed in this application is innova- tive, in the applicants’ opinion, because it rigorously develops thorough spatiotemporal air pollution data that captures temporal and spatial air pollution trends and analyzes a deeply phenotyped ALS and control cohort from the industrial Midwest. The proposed research is significant because it will provide critical data on the dis- tinct types of air pollution, immune profiles, and immune pathways associated with ALS risk, progression, and survival. Ultimately, as air pollution is a modifiable risk factor, knowledge from this proposal can guide preven- tion efforts, therapeutic targets, and blood-based biomarkers for use in clinical studies.