Impact of Geospatial Factors and Environmental Pollutants on Amyotrophic Lateral Sclerosis in the State of Michigan

地理空间因素和环境污染物对密歇根州肌萎缩侧索硬化症的影响

• 批准号: 9312942
• 负责人: Stephen Goutman
• 金额: $ 20.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312942
• 关键词: Address; Affect; Amyotrophic Lateral Sclerosis; Blood; Case-Control Studies; Characteristics; Clinic; Clinical; Collaborations; Complex; Cycad; DNA Sequence Alteration; Data; Development; Disease; Disease Outcome; Disease Progression; Environment; Environmental Exposure; Environmental Impact; Environmental Pollutants; Environmental Pollution; Environmental Risk Factor; Epigenetic Process; Excision; Exposure to; Functional disorder; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Goals; Hazardous Waste Sites; Heterogeneity; Incidence; Individual; Knowledge; Measures; Methods; Michigan; Modeling; Motor Neurons; Nerve Degeneration; Neurodegenerative Disorders; Newly Diagnosed; Occupational; Outcome; Pathogenesis; Patients; Persons; Phenotype; Play; Population; Predisposition; Prevalence; Probability; Proportional Hazards Models; Public Health; Questionnaires; Recording of previous events; Registries; Regression Analysis; Reporting; Research; Risk; Risk Factors; Role; Site; Testing; Therapeutic; Time; Toxic Environmental Substances; Universities; Variant; biobank; biomarker discovery; burden of illness; disorder prevention; disorder risk; geographic difference; improved; innovation; insight; modifiable risk; motor neuron degeneration; persistent organic pollutants; pleiotropism; pollutant; prevent; translational impact

Project Summary/Abstract There is a fundamental gap in understanding how environmental exposures affect the development and clinical expression of amyotrophic lateral sclerosis (ALS). Continued existence of this gap represents an important problem, because until it is filled, understanding how specific environmental toxins affect the pathophysiology of ALS (1) hampers the ability to delineate ALS mechanisms and thereby limit treatment opportunities and (2) prevents the removal of modifiable risk factors from the environment. The long-term goals are to determine the influence of environmental toxins on the genetic susceptibility and pathogenesis of ALS, contextualize our data to support the National ALS registry, and promote therapeutic and biomarker discovery. The overall objective of this application is to identify persistent organic pollutants that associate with ALS disease expression. The central hypothesis is that persistent organic pollutants alter ALS incidence and disease factors such as surviv- al. The rationale for the proposed research is that discovering and delineating the impact of environmental tox- ins on ALS can identify a modifiable disease risk and also inform our understanding of the disease’s patho- physiology. Guided by strong preliminary data, this hypothesis will be tested by pursing two specific aims: 1) Determine how exposure to persistent organic pollutants modifies ALS disease expression in patients followed at the University of Michigan ALS Clinic; and 2) Expand the assessments of ALS and environmental exposures statewide to determine if geospatial clusters of ALS occur in Michigan and characterize their relationship to known sites of environmental pollution. Under the first aim the impact of environmental exposures--derived via a detailed questionnaire combined with measured persistent organic pollutant levels in blood--on region of on- set, survival, and disease progression will be determined. Under the second aim, a case-control study, com- prised of all newly diagnosed individuals with ALS and healthy controls, will determine the presence of geospa- tial clusters of ALS in State of Michigan. The proposed research is innovative, in the applicant’s opinion, be- cause it represents a substantive departure from the status quo by explicitly identifying how persistent organic pollutants alter ALS disease expression and how geospatial factors, such as persistent environmental pollu- tants, alter ALS susceptibility which will pave the way for improved pathophysiologic studies on ALS. New re- search horizons are expected to become attainable as a result. The proposed research is significant, because it will identify factors that can mitigate the risk of developing ALS and furthermore guide future studies on new pathophysiologic mechanisms of ALS. Ultimately, such knowledge has the potential to improve the pathophys- iologic understanding of ALS and other neurodegenerative diseases.

项目总结/摘要 在理解环境暴露如何影响发育和临床方面存在根本性差距 肌萎缩侧索硬化症（ALS）的表达。这一差距的持续存在， 问题，因为直到它被填满，了解特定的环境毒素如何影响病理生理学 （1）阻碍了描述ALS机制的能力，从而限制了治疗机会，以及（2） 防止从环境中去除可改变的风险因素。长期目标是确定 环境毒素对ALS遗传易感性和发病机制的影响， 支持国家ALS登记，促进治疗和生物标志物的发现。总体目标 本申请的目的是鉴定与ALS疾病表达相关的持久性有机污染物。的 中心假设是，持久性有机污染物改变ALS发病率和疾病因素，如生存， al.提出研究的理由是，发现和描述环境毒性的影响- ALS的研究可以确定一种可改变的疾病风险，并告知我们对疾病病理的理解， physiology.在强有力的初步数据的指导下，这一假设将通过追求两个具体目标来检验：1） 确定暴露于持久性有机污染物如何改变患者的ALS疾病表达， 在密歇根大学ALS诊所;和2）扩大ALS和环境暴露的评估 全州范围内确定ALS的地理空间集群是否发生在密歇根州，并描述它们与 已知的环境污染点。在第一个目标下，环境照射的影响-通过 结合血液中持久性有机污染物测量水平的详细调查表-关于2008 - 2009年 将确定集、存活率和疾病进展。根据第二个目标，病例对照研究，com- 对所有新诊断的ALS患者和健康对照者进行检查，将确定geospa的存在， 在密歇根州的ALS集群。申请人认为，拟议的研究具有创新性， 因为它代表了一个实质性的偏离现状，明确确定如何持久的有机 污染物改变ALS疾病的表达，以及地理空间因素，如持续的环境污染， 这些药物改变了ALS的易感性，这将为改善ALS的病理生理学研究铺平道路。新的重新- 预计搜索范围将因此变得可实现。这项研究意义重大，因为 它将确定可以减轻ALS发病风险的因素，并进一步指导未来新的研究 ALS的病理生理机制。最终，这些知识有可能改善病理学- ALS和其他神经退行性疾病的生物学理解。