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

美国四分之一的慢性阻塞性肺疾病(COPD)患者没有吸烟史。职业对慢性阻塞性肺疾病的发展贡献很大。内毒素是一种普遍存在的、缺乏认识的环境和职业暴露，可能导致非烟草相关的COPD。在最近的研究中，在人类和小鼠模型中，慢性吸入性内毒素与阻塞性肺疾病的发生有关。尽管内毒素相关的肺部疾病很重要，但它还没有得到很好的研究。 本研究的主要目的是探讨长期内毒素暴露所致慢性阻塞性肺疾病发生的生物学基础。我们假设特定的基因和按功能或相互作用分组的基因在内毒素相关肺部疾病的发展中发挥作用。为了验证这一假设，我们将通过整合暴露-新雇用的棉纺织工人队列中的高密度定制基因分型数据与表型验证的慢性内毒素暴露小鼠模型中的基因表达数据来选择候选单核苷酸多态(SNPs)和相关基因。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，对未能达到全基因组意义的SNP进行重新排序。然后，候选地区将在长期暴露的棉纺织工人队列中进行测试。然后，验证区域将被注释为推定的生物功能，并将对所有验证区域进行交互分析，以推断慢性吸入内毒素和阻塞性肺疾病的致病机制。 作为研究培训计划的一部分，首席调查员将完成公共卫生硕士学位，重点是定量方法，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。这项研究项目将在一位在过去30年里研究内毒素相关肺部疾病的遗传流行病学知名研究员的指导下进行。

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.