Identify and Evaluate Potential Risk Factors for Amyotrophic Lateral Sclerosis - A Unique Contribution from Sweden

项目摘要 服兵役，创伤性脑损伤（TBI），慢性神经炎症和感染都被认为是 肌萎缩侧索硬化症（ALS）的潜在危险因素。然而，现有的知识库 受系统误差和随机误差的限制。此外，将这些风险联系在一起的基本机制 因素以及ALS的发生和发展在很大程度上仍然是未知的。 最终目标是为高危人群的疾病预防提供重要的新知识 并确定新的治疗靶点，这项研究计划的总体目标是利用广泛的 数据和生物标本收集在一个独特的瑞典国家ALS登记处，以确定和评估军事 服务，TBI，精神障碍（作为慢性神经炎症的代表）和感染作为潜在风险， ALS的预后因素，重点是了解它们与个体遗传易感性的相互作用， ALS、化学品暴露（在人体组织中测量的> 10，000种化学品及其代谢物）和肠道 微生物组我们将在有毒物质和疾病登记处复制其中的一些发现 美国毒物与疾病登记署（ATSDR）实施了美国国家ALS登记处，我们已经从ALS患者中收集了样本。 在具体目标I中，我们将评估服兵役、TBI、精神障碍和感染对风险的作用。 和ALS的预后，使用前瞻性和独立收集的数据，从瑞典国家卫生 登记（包括运动神经元疾病[MND]登记），通过对比不同临床表现的ALS患者， 表型与三个对照组，即无疾病的全同胞，配偶，年龄和性别匹配 人口控制。在具体的目标II中，我们将描述不同类型之间相互作用的作用。 暴露和1）个体对ALS的遗传易感性，2）化学暴露和3）ALS的肠道微生物组 并在美国复制研究结果。在具体的目标III中，我们将开发一种分子 基于表型的精确医学工具，允许根据ALS患者的 ALS的遗传易感性和临床措施，以提供一种新的方法来更好地预测 疾病进展。 该项目的发现有望促进我们对ALS作为一种疾病的理解，并提供新的 疾病预防和治疗知识，完全支持ATSDR国家ALS登记处的使命。 研究结果还将有助于ATSDR更好地优先考虑未来研究计划的主题，并为 为ALS患者制定新的ATSDR ALS登记风险因素调查。

Project summary Military service, traumatic brain injuries (TBI), chronic neuroinflammation and infections have all been suggested as potential risk factors for amyotrophic lateral sclerosis (ALS). The currently existing knowledge base is however limited by systematic and random errors. Moreover, the underlying mechanisms linking together those risk factors and the initiation and progression of ALS are still largely unknown. With the ultimate goal of providing important new knowledge for disease prevention among high-risk individuals and identifying novel therapeutic targets, the overarching aim of this research program is to use the extensive data and biospecimens collected in a unique Swedish national ALS registry, to identify and evaluate military service, TBI, mental disorders (as a proxy for chronic neuroinflammation), and infections as potential risk and prognostic factors for ALS, focusing on understanding their interactions with individual genetic susceptibility to ALS, chemical exposures (>10,000 chemicals and their metabolites measured in human tissue), and gut microbiome. We will replicate some of these findings in the Agency for Toxic Substances and Disease Registry (ATSDR) implemented US National ALS Registry where we have already collected samples from ALS patients. In the specific Aim I, we will assess the roles of military service, TBI, mental disorders and infections on the risk and prognosis of ALS, using prospectively and independently collected data from the Swedish national health registers (including the Motor Neuron Disease [MND] Registry), by contrasting ALS patients of different clinical phenotypes with three control groups, namely disease-free full siblings, spouses, and age- and sex-matched population controls. In the specific Aim II, we will characterize the role of interactions between different exposures and 1) individual genetic susceptibility to ALS, 2) chemical exposures, and 3) gut microbiome on ALS in Sweden and replicate findings in the United States. In the specific Aim III, we will develop a molecular phenotyping-based precision medicine tool to allow precise stratification of ALS patients based on their exposome, genetic susceptibility to ALS, and clinical measures, to provide a novel approach to better predicting disease progression. Findings from this project are expected to advance our understanding of ALS as a disease and provide new knowledge for disease prevention and treatment, fully supporting the ATSDR National ALS Registry's mission. The findings will also help ATSDR better prioritize topics for future research initiatives and inform the development of new ATSDR ALS Registry risk factor surveys for persons with ALS.