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: 9912765
• 负责人: Stephen Goutman
• 金额: $ 20.21万
• 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/9912765
• 关键词: ALS patients; 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.

项目摘要/摘要 在理解环境暴露如何影响发育和临床方面存在着根本的差距。 肌萎缩侧索硬化症的表达。这种差距的持续存在代表着一个重要的 问题，因为在填满之前，了解特定的环境毒素是如何影响病理生理的 肌萎缩侧索硬化症(1)阻碍了描述肌萎缩侧索硬化症机制的能力，从而限制了治疗机会和(2) 防止从环境中移除可更改的风险因素。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 支持国家肌萎缩侧索硬化症注册，并促进治疗和生物标记物的发现。总体目标 这一应用的目的是识别与ALS疾病表达相关的持久性有机污染物。这个 中心假设是持久性有机污染物改变ALS的发病率和疾病因素，如存活- 艾尔这项拟议研究的基本原理是，发现和描述环境毒素的影响- 肌萎缩侧索硬化症上的INS可以识别可改变的疾病风险，还可以帮助我们理解疾病的病理机制。 生理学。在强劲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) 确定持久性有机污染物暴露如何改变随访患者的ALS疾病表现 在密歇根大学肌萎缩侧索硬化症诊所；以及2)扩大对肌萎缩侧索硬化症和环境暴露的评估 以确定密歇根州是否出现肌萎缩侧索硬化症的地理空间集群，并表征它们与 已知的环境污染地点。在第一个目标下，环境暴露的影响--通过 一份详细的调查问卷，结合血液中持久性有机污染物的测量水平-关于On-On区域 SET、存活率和疾病进展将被确定。在第二个目标下，一项病例对照研究，COM。 对所有新诊断的ALS患者和健康对照进行调查，将确定地球空间的存在- 密歇根州的肌萎缩侧索硬化症患者群。申请人认为，拟议的研究是创新的，是- 因为它代表着对现状的实质性偏离，因为它明确地确定了持久的有机 污染物改变了ALS疾病的表现，以及持续的环境污染等地理空间因素是如何改变ALS疾病的 药物，改变ALS的易感性，这将为改善ALS的病理生理研究铺平道路。新的重新- 因此，预计搜索范围将变得可以实现。这项拟议的研究意义重大，因为 它将确定可以降低ALS风险的因素，并进一步指导未来对新的 肌萎缩侧索硬化症的病理生理机制最终，这样的知识有可能改善病理物理-- 对肌萎缩侧索硬化症和其他神经退行性疾病的生物学理解。