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

小鼠和人类模型中慢性内毒素暴露引起的肺部疾病

基本信息

批准号：
8608942
负责人：
Peggy Sue Lai
金额：
$ 1.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-15 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8608942
关键词：
Animal Model Bacterial Toxins Bioinformatics Biological Process Biology Biometry Breathing Chronic Chronic Airflow Obstruction Chronic Obstructive Airway Disease Chronic lung disease Cohort Analysis Data Deposition Development Diagnosis Disease Drops Drug Targeting Endotoxins Environmental and Occupational Exposure Epidemiology Exposure to Extracellular Matrix Family suidae Farming environment Foundations Future Gene Expression Gene Expression Profile Genes Genome Genomics Genotype Gossypium Human Individual Institutes Lead Lung Lung diseases Maps Master of Public Health Mentorship Methods Modeling Molecular Mus Network-based Obstruction Obstructive Lung Diseases Occupational Occupational Exposure Pathologic Processes Pathway Analysis Pathway interactions Patients Pharmacotherapy Plants Play Process Publishing Pulmonary Emphysema Pulmonary Function Test/Forced Expiratory Volume 1 Research Personnel Research Project Grants Research Training Role Severities Signal Pathway Single Nucleotide Polymorphism Smoke Smoking History Techniques Testing Textiles Tissue-Specific Gene Expression Tobacco Training Programs United States Variant Work Workplace airway remodeling base cohort density genetic epidemiology genome-wide human data novel protein protein interaction response risk variant sewage treatment skills toll-like receptor 4 tool

项目摘要

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.

在美国，四分之一的慢性阻塞性肺病（COPD）患者没有吸烟史。职业对慢性阻塞性肺病的发展有显着的影响。内毒素是一种普遍存在且未被充分认识的环境和职业暴露，可能导致非烟草相关的慢性阻塞性肺病。最近的研究表明，慢性吸入内毒素与人类和小鼠模型中阻塞性肺病的发生有关。尽管内毒素相关肺部疾病很重要，但尚未得到充分研究。本研究的主要目的是调查由于长期接触内毒素而导致慢性阻塞性肺病发展的生物学基础。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肺部疾病的发展中发挥作用。为了检验这一假设，我们将通过将新接触的棉纺织工人群体中的高密度定制基因分型数据与经过表型验证的小鼠模型中的基因表达数据相结合，选择候选单核苷酸多态性（SNP）和相关基因。慢性内毒素暴露。我们还将使用功能注释和蛋白质-蛋白质相互作用等上下文信息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“长期”棉纺织工人群体中进行测试。然后将对经过验证的区域进行假定的生物学功能注释，并对所有经过验证的区域进行相互作用分析，以推断慢性吸入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，首席研究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。该研究项目将在一位资深遗传流行病学研究者的指导下进行，该研究者在过去 30 年里一直在研究与内毒素相关的肺部疾病。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin.

DOI：
10.1371/journal.pone.0062910
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Lai PS;Hofmann O;Baron RM;Cernadas M;Meng QR;Bresler HS;Brass DM;Yang IV;Schwartz DA;Christiani DC;Hide W
通讯作者：
Hide W

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