Mapping the ALS Exposome to Gain New Insights into Disease Risk and Pathogenesis

摘要 肌萎缩侧索硬化症（ALS）是一种进行性和致命的神经退行性疾病，具有复杂的非神经系统疾病， 已知的发病机制。最近的证据支持基因-时间-环境假说， 当暴露在遗传风险特征上时，会引发神经退化。支持这一前提， 长期不利的环境暴露与ALS风险和进展有关;我们已经表明， 测量和报告的农药暴露强烈增加ALS风险，高水平的持久性或- 有机污染物（POP）降低了密歇根州ALS受试者的ALS生存率。因此，有必要去- 列出了“ALS危险组”，定义为导致ALS风险的环境暴露的寿命。在 我们的目标是通过提高对污染物混合的洞察力来改进我们的ALS麻烦模型， 与ALS相关的疾病占遗传风险，识别暴露的易感期， 在易于评估的生物流体中进行毒素测量，并确定这些 环境毒素被吸收到中枢神经系统（CNS）中，以提高对环境的洞察力。 ALS的基因-时间-环境假说。我们的中心假设是， 生物流体和CNS组织将推进ALS发病机理的模型。在目标1中，我们将更好地描述 通过测量从ALS亚组纵向获得的生物样品中的环境毒素， 来自密歇根大学ALS患者库的数据以及年龄和性别匹配的对照， 密歇根州产生洞察污染物的混合物，有助于疾病的风险和生存， 通过多基因风险评分计算遗传易感性。在目标2中，我们将评估住宅和住宅- 与ALS风险和生存相关的历史，同时也将暴露历史与毒素相关， 目标1中的措施，以全面了解ALS关键的暴露混合物和时间窗口 风险最后，在目标3中，我们将定量ALS中的环境毒素和重金属，并控制CNS组织。 并将外周改变与ALS CNS组织和关键暴露窗口中观察到的变化联系起来 从而确定可能导致ALS发病的环境危险因素。总的来说， 这些目标的顺利完成将通过识别ALS疾病产生重要的积极转化影响 与职业和环境暴露相关的风险因素，同时考虑遗传易感性， 能力因此，这项建议将扩大我们对ALS基因组的理解， 风险，确定构成公共健康风险的毒素，确定与暴露有关的职业，并建立一个 框架来测试这些暴露在其他神经退行性疾病。这种对肌萎缩侧索硬化症的理解 卫生部将支持急需的公共卫生干预措施，以针对这一地区可改变的疾病风险因素。 致命的紊乱

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease with complex un- known pathogenesis. Recent evidence supports a gene-time-environment hypothesis whereby environmental exposures trigger neurodegeneration when superimposed on a genetic risk profile. Supporting this premise, long-term adverse environmental exposures are linked to ALS risk and progression; we have shown that measured and reported pesticide exposures strongly increase ALS risk and that high levels of persistent or- ganic pollutants (POPs) decrease ALS survival in ALS subjects in Michigan. Therefore, there is a need to de- lineate the “ALS exposome,” defined as the lifetime of environmental exposures that contributes to ALS risk. In this proposal, our objectives are to improve our ALS exposome model by enhancing insight into pollutant mix- tures associated with ALS accounting for genetic risk, identifying periods of susceptibility to exposures, corre- lating toxin measurements in easily assessable biofluids with epidemiologic data, and identifying whether these environmental toxins are absorbed into the central nervous system (CNS) in order to improve insight into the gene-time-environment hypothesis in ALS. Our central hypothesis is that identifying environmental pollutants in biofluids and CNS tissues will advance models of ALS pathogenesis. In Aim 1, we will better characterize the ALS exposome by measuring environmental toxins in biological samples obtained longitudinally from ALS sub- jects from the University of Michigan ALS Patient Repository and age- and sex-matched controls across the State of Michigan to yield insight into the pollutant mixtures that contribute to disease risk and survival, ac- counting for genetic susceptibility via polygenic risk scores. In Aim 2, we will evaluate residential and occupa- tional histories for association with ALS risk and survival, while also correlating exposure histories to toxin measures from Aim 1, to gain comprehensive insight into exposure mixtures and time windows critical for ALS risk. Finally, in Aim 3, we will quantitate environmental toxins and heavy metals in ALS and control CNS tis- sues, and link peripheral alterations with observed changes in ALS CNS tissue and critical exposure windows to thereby ascertain environmental risk factors that potentially contribute to ALS pathogenesis. Overall, suc- cessful completion of these aims will have an important positive translational impact by identifying ALS disease risk factors associated with occupational and environmental exposures, while accounting for genetic suscepti- bility. This proposal will therefore expand our understanding of the ALS exposome in the context of genetic risk, identify toxins that pose a public health risk, identify occupations linked to exposures, and establish a framework to test for these exposures in other neurodegenerative diseases. This understanding of the ALS exposome will support much-needed public health interventions to target modifiable disease risk factors in this lethal disorder.