Lung disease due to chronic endotoxin exposure in mouse and human models

在美国，四分之一的慢性阻塞性肺疾病（COPD）患者没有吸烟史。职业对COPD的发展有重要影响。内毒素是一种普遍存在但认识不足的环境和职业暴露，可能导致非烟草相关的COPD。在最近的研究中，慢性吸入性内毒素与人类和小鼠模型中阻塞性肺疾病的发展有关。尽管内毒素相关的肺部疾病的重要性，它还没有得到很好的研究。 本研究的主要目的是研究长期内毒素暴露导致慢性阻塞性肺疾病发生的生物学基础。我们假设特定基因和按功能或相互作用分组的基因在内毒素相关性肺病的发展中起作用。为了验证这一假设，我们将选择候选单核苷酸多态性（SNP）和相关基因，通过整合高密度定制的基因分型数据，在一个新雇用的棉纺织工人队列中的基因表达数据，在表型验证的小鼠模型的慢性内毒素暴露。我们还将使用上下文信息，如功能注释和蛋白质-蛋白质相互作用，重新排序SNPs，未能达到全基因组的意义。然后，候选区域将在长期暴露的“长期”棉纺织工人队列中进行测试。然后将对验证区域进行推定生物学功能注释，并对所有验证区域进行相互作用分析B，以推断慢性吸入性内毒素和阻塞性肺病的致病机制。 作为研究培训计划的一部分，主要研究人员将完成公共卫生硕士学位，专注于定量方法，以获得必要的流行病学和生物统计学技能以及相关的生物信息学工具。本研究项目将在遗传流行病学研究者的指导下进行，该研究者在过去30年中研究了内毒素相关的肺部疾病。

A quarter of patients with chronic obstructive pulmonary disease (COPD) in the United States have no history of smoking. The occupational contribution to development of COPD is significant. Endotoxin is a ubiquitous and poorly recognized environmental and occupational exposure that may cause non-tobacco related COPD. In recent studies, chronic inhalational endotoxin has been associated with the development of obstructive lung disease in both humans and murine models. Despite the importance of endotoxin related lung disease, it has not been well studied. The primary objective of this study is to investigate the biology underlying the development of chronic obstructive lung disease due to long term endotoxin exposure. We hypothesize that specific genes and genes grouped by function or interaction play a role in the development of endotoxin related lung disease. To test this hypothesis, we will select candidate single nucleotide polymorphisms (SNPs) and associated genes by integrating high density customized genotyping data in an exposure-naove "newly hired" cohort of cotton textile workers with gene expression data in a phenotypically validated murine model of chronic endotoxin exposure. Wewill also use contextual information such as functional annotation and protein-protein interactions to re-rank SNPs that fail to reach genome wide significance. Candidate regions will then be tested in a chronically exposed "long term" cohort of cotton textile workers. Validated regions will then be annotated for putative biological function, and an interaction analysis will b performed on all validated regions to infer disease causing mechanisms underlying chronic inhaled endotoxin and obstructive lung disease. As part of the research training program, the principle investigator will complete a Master of Public Health with a concentration in Quantitative Methods in order to acquire the necessary epidemiology and biostatistics skills, as well as relevant bioinformatics tools. This research project will be performed under the mentorship of an established investigator in genetic epidemiology who has studied endotoxin-related lung disease for the past 3 decades.