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性神经退行性疾病，其临床表现复杂多样。 已知的发病机制。最近的证据支持基因-时间-环境假说 当暴露叠加在遗传风险谱上时，会引发神经退化。支持这一前提， 长期的不良环境暴露与肌萎缩侧索硬化症的风险和进展有关；我们已经证明 测量和报告的杀虫剂暴露强烈增加了ALS的风险，高水平的持久性或- 有机污染物(POP)降低了密歇根州ALS患者的ALS存活率。因此，有必要取消- 划出“肌萎缩侧索硬化症暴露组”，定义为导致肌萎缩侧索硬化症风险的环境暴露的生命周期。在……里面 这项建议，我们的目标是通过加强对污染物混合的洞察来改进我们的ALS暴露组模型- 与肌萎缩侧索硬化症相关的基因风险，确定暴露的敏感期，相应 用流行病学数据对易于评估的生物体液中的毒素进行最新测量，并确定这些 环境毒素被吸收到中枢神经系统(CNS)中，以便更好地了解 ALS的基因-时间-环境假说。我们的中心假设是，在 生物体液和中枢神经系统组织将推动ALS发病模型的发展。在目标1中，我们将更好地描述 通过测量从ALS亚单位纵向获得的生物样本中的环境毒素来暴露ALS 来自密歇根大学肌萎缩侧索硬化症患者资料库的对象和年龄和性别匹配的对照组 密歇根州为深入了解有助于疾病风险和生存的污染物混合物，Ac. 通过多基因风险评分计算遗传易感性。在目标2中，我们将评估住宅和居住率- 与肌萎缩侧索硬化症风险和生存相关的历史，同时也将暴露史与毒素相关 从目标1开始采取措施，全面了解暴露混合物和对ALS至关重要的时间窗口 风险。最后，在目标3中，我们将对ALS中的环境毒素和重金属进行量化，并控制CNS- 并将外周改变与观察到的ALS CNS组织和临界暴露窗口的变化联系起来 从而确定可能导致ALS发病的环境危险因素。总体来说，Suc- 成功完成这些目标将通过识别ALS疾病产生重要的积极翻译影响 与职业和环境暴露相关的风险因素，同时解释了遗传易感性- 保佑。因此，这一建议将扩大我们在遗传背景下对ALS暴露组的理解 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 在其他神经退行性疾病中测试这些暴露的框架。这种对ALS的理解 Exposome将支持急需的公共卫生干预措施，以针对可改变的疾病风险因素 致命性障碍。

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.