Endotoxin, the airway transcriptome, and obstructive lung disease

内毒素、气道转录组和阻塞性肺病

• 批准号: 8739644
• 负责人: Peggy Sue Lai
• 金额: $ 15.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-23 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739644
• 关键词: Accounting; Acute; Address; Adult; Affect; American; Area; Asthma; Award; Biological; Biological Markers; Biomass; Biometry; Bronchi; Burn injury; Byssinosis; Categories; Characteristics; Chest; Child; Childhood Asthma; Chronic; Chronic Obstructive Airway Disease; Clinical; Clinical Medicine; Closed Cohort Studies; Cluster Analysis; Cohort Studies; Complement; Consent; Critical Care; Development; Development Plans; Diagnosis; Disease; Endotoxins; Environment; Environmental Epidemiology; Environmental Exposure; Epithelial Cells; Equipment; Exposure to; Funding; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Gossypium; Gram-Negative Bacteria; Home environment; Hospitalization; Indoor Air Pollution; Inflammatory; Institution; Knowledge; Lead; Leadership; Learning; Link; Lung; Lung diseases; Machine Learning; Master of Public Health; Measures; Mentors; Mentorship; Methods; Microarray Analysis; Molecular; Molecular Epidemiology; Morbidity - disease rate; Nasal Epithelium; Nose; Obstruction; Obstructive Lung Diseases; Occupational; Occupations; Output; Pathway interactions; Patients; Phenotype; Predisposition; Pulmonary Emphysema; Recording of previous events; Recruitment Activity; Research; Research Infrastructure; Research Personnel; Research Training; Resources; Respiratory physiology; Risk; Sampling; School-Age Population; Schools; Severities; Silk; Smoking; Symptoms; Syndrome; Testing; Textiles; Time; Tobacco; Tobacco smoke; Training; United States; United States National Institutes of Health; Visit; Work; X-Ray Computed Tomography; airway epithelium; attenuation; base; bronchial epithelium; career; career development; cohort; data mining; disorder subtype; elementary school; environmental endotoxin; experience; inner city; insight; multidisciplinary; novel; outcome forecast; patient oriented research; public health relevance; respiratory; response; skills; sound; symposium; trend

DESCRIPTION (provided by applicant): Research Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory lung diseases that affect an estimated 35 million Americans. Endotoxin is derived from gram negative bacteria, and has been associated with both asthma and COPD. Endotoxin is almost universally present, and has been found at high levels in tobacco smoke, homes burning biomass fuel, in the context of various occupations especially cotton textile work, and more recently as part of indoor air pollution in schools. We do not fully understand how endotoxin can lead to development or worsening of asthma and COPD. Recent technologic advances have allowed one to simultaneously identify changes in expression of over 14K genes using microarrays. Studies comparing gene expression changes from invasive samples taken from the bronchi (lower airways) and non- invasive samples from the nose (upper airways) have shown many similarities. Studying how endotoxin affects the airways using gene expression changes is an important opportunity to further understand the relationship between endotoxin and lung disease. In this career development proposal, the applicant hypothesizes that endotoxin leads to distinct gene expression changes in the airways. These gene expression changes reflect underlying dysregulated pathways in lung disease that can serve as a biomarker for susceptibility to disease exacerbation, disease development, or clinically important subtypes of lung disease. She proposes to examine the impact of current high endotoxin exposure on airway gene expression in a cohort of inner-city elementary school children with and without asthma. She then proposes to evaluate whether prior endotoxin exposure leads to persistent changes in airway gene expression, even after years of exposure cessation, in a cohort of textile workers. Finally, she proposes to evaluate whether these gene expression changes are markers for important disease-specific subphenotypes, specifically "exacerbation prone" asthmatics in the school study and "emphysema type" COPD in the textile study. These studies take advantage of the sound study infrastructure present in two already existing and unique cohort studies, and will provide novel insights into the ways nasal gene expression can be used to understand the effects of chronic endotoxin exposure in a field setting. The successful completion of this research will help us understand the genes and biological pathways that are affected by chronic high endotoxin exposure, identify people who are susceptible to endotoxin-related asthma exacerbations, determine whether the type of COPD (emphysema vs. airways disease) can be identified using a simple gene expression based test, and may lead the way to the development of new therapies for endotoxin related lung disease. Additionally, it further characterizes the importance of school endotoxin exposure in asthma morbidity, and may shift the focus from home to school environmental controls for children with asthma. Candidate The applicant's long-term career goal is to become an independent clinical/translational NIH funded investigator focused on patient-oriented research in environmental lung disease. In order to achieve this goal, her short-term career objectives are to obtain further didactic training in environmental epidemiology, advanced biostatistics, genomics, and data mining, as well as practical skills in building a cohort, exposure assessment, obtaining biospecimens, nucleic extraction, selection of appropriate microarray technology, and analytic work in interpreting the output. This will be accomplished with formal classes that complement the candidate's prior coursework in completing a Master of Public Health, fieldwork and collaborative work to learn how to measure environmental endotoxin exposure and to recruit, consent, and maintain a cohort, benchwork using molecular methods, attendance at institutional and national conferences, and guidance from established mentors and a multidisciplinary advisory board with the relevant expertise. This will result in a unique combination of practical skills and scientific knowledge that will help her achieve independence from her mentorship team and prepare her to achieve her long-term career goal. Environment The applicant will perform her research training and career development activities at world-renowned major academic institutions. The division in which she will work is one that has a collaborative environment with both a rich research environment and an intense clinical focus, and has an outstanding history of mentorship, leadership in pulmonary and critical care medicine, and clinical excellence. Her institution is very invested in the applicant's successful career development, and will make available all the facilities, resources, and equipment needed for her career development and proposed research. Her mentors are nationally and internationally renowned experts in pediatric asthma and environmental and molecular epidemiology, and will provide full access to the resources accompanying two unique cohorts of endotoxin exposed children and adults.

描述（由申请人提供）： 研究 哮喘和慢性阻塞性肺病 (COPD) 是影响大约 3500 万美国人的慢性炎症性肺部疾病。内毒素源自革兰氏阴性细菌，与哮喘和慢性阻塞性肺病有关。内毒素几乎普遍存在，在烟草烟雾、燃烧生物质燃料的家庭、各种职业（尤其是棉纺织工作）以及最近作为学校室内空气污染的一部分中都发现了高含量的内毒素。我们并不完全了解内毒素如何导致哮喘和慢性阻塞性肺病的发生或恶化。最近的技术进步使得人们能够使用微阵列同时识别超过 14K 基因的表达变化。比较取自支气管（下呼吸道）的侵入性样本和取自鼻子（上呼吸道）的非侵入性样本的基因表达变化的研究显示出许多相似之处。利用基因表达变化研究内毒素如何影响气道是进一步了解内毒素与肺部疾病之间关系的重要机会。在这份职业发展提案中，申请人假设内毒素会导致气道中明显的基因表达变化。这些基因表达变化反映了肺病中潜在的失调途径，可以作为疾病恶化、疾病发展或肺病临床重要亚型易感性的生物标志物。她提议检查当前高内毒素暴露对一组患有或不患有哮喘的市中心小学生气道基因表达的影响。然后，她建议评估一组纺织工人中先前接触过内毒素是否会导致气道基因表达的持续变化，即使在停止接触内毒素多年后也是如此。最后，她建议评估这些基因表达变化是否是重要的疾病特异性亚表型的标志，特别是学校研究中的“易恶化”哮喘和纺织品研究中的“肺气肿型”慢性阻塞性肺病。这些研究利用了两项现有且独特的队列研究中存在的健全的研究基础设施，并将为如何使用鼻基因表达来了解现场环境中慢性内毒素暴露的影响提供新的见解。这项研究的成功完成将帮助我们了解受慢性高内毒素暴露影响的基因和生物学途径，识别易受内毒素相关哮喘急性加重影响的人群，确定COPD（肺气肿与气道疾病）的类型是否可以缓解。使用简单的基于基因表达的测试即可识别，并可能为开发内毒素相关肺部疾病的新疗法开辟道路。此外，它进一步描述了学校内毒素暴露在哮喘发病中的重要性，并可能将哮喘儿童的重点从家庭环境控制转移到学校。候选人 申请人的长期职业目标是成为一名独立的临床/转化 NIH 资助的研究者，专注于以患者为导向的环境肺病研究。为了实现这一目标，她的短期职业目标是获得环境流行病学、高级生物统计学、基因组学和数据挖掘方面的进一步教学培训，以及建立队列、暴露评估、获取生物样本、核酸提取的实践技能、选择适当的微阵列技术以及解释输出的分析工作。这将通过正式课程来完成，这些课程补充了候选人之前完成公共卫生硕士的课程作业、实地考察和协作工作，以学习如何测量环境内毒素暴露以及招募、同意和维持队列、使用分子方法的基准工作、出勤率在机构和国家会议上，以及来自既定导师和具有相关专业知识的多学科咨询委员会的指导。这将带来实践技能和科学知识的独特结合，帮助她摆脱导师团队的束缚，并为实现长期职业目标做好准备。环境申请人将在世界知名的主要学术机构进行研究培训和职业发展活动。她将工作的部门是一个拥有丰富研究环境和强烈临床关注的协作环境的部门，并且在肺病和重症监护医学领域的指导、领导和临床卓越方面拥有杰出的历史。她的机构对申请人的成功职业发展投入很大，并将为其职业发展和拟议研究提供所需的所有设施、资源和设备。她的导师是国内和国际知名的儿科哮喘、环境和分子流行病学专家，并将为两个独特的内毒素暴露儿童和成人群体提供全面的资源。