Endotoxin, the airway transcriptome, and obstructive lung disease

描述(由申请人提供)： 研究性哮喘和慢性阻塞性肺疾病(COPD)是慢性炎症性肺部疾病，估计有3500万美国人受到影响。内毒素来自革兰氏阴性细菌，与哮喘和慢性阻塞性肺疾病有关。内毒素几乎普遍存在，在烟草烟雾、燃烧生物质燃料的家庭、各种职业背景下，特别是棉纺织工作中，以及最近作为学校室内空气污染的一部分，都发现了高水平的内毒素。我们还不完全了解内毒素是如何导致哮喘和COPD的发展或恶化的。最近的技术进步使人们能够使用微阵列同时识别超过14K个基因表达的变化。比较来自支气管(下呼吸道)的侵袭性样本和来自鼻子(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呼吸道，是进一步了解内毒素与肺部疾病关系的重要契机。在这份职业发展计划中，申请者假设内毒素会导致呼吸道中明显的基因表达变化。这些基因表达的变化反映了肺部疾病潜在的失调途径，可以作为疾病恶化、疾病发展或临床上重要的肺部疾病亚型的易感性的生物标志物。她建议检查目前高内毒素暴露对患有和不患有哮喘的市中心小学生队列中呼吸道基因表达的影响。然后，她建议评估先前的内毒素暴露是否会导致呼吸道基因表达的持续变化，即使在多年的暴露停止后，也是如此，在一组纺织工人中。最后，她建议评估这些基因表达变化是否是重要疾病特定亚型的标志，特别是在学校研究中的“易加重”哮喘患者和在纺织研究中的“肺气肿类型”COPD患者。这些研究利用了两项已经存在的独特的队列研究中现有的健全的研究基础设施，并将为如何利用鼻部基因表达来理解现场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有助于我们了解受慢性高内毒素暴露影响的基因和生物途径，识别内毒素相关哮喘恶化的易感人群，确定COPD(肺气肿与呼吸道疾病)的类型是否可以通过简单的基于基因表达的测试来识别，并可能引领内毒素相关肺部疾病的新疗法的发展。此外，它进一步表征了学校内毒素暴露在哮喘发病率中的重要性，并可能将重点从家庭转移到学校对哮喘儿童的环境控制。申请人的长期职业目标是成为美国国立卫生研究院资助的独立临床/转化性研究人员，专注于以患者为中心的环境肺病研究。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，以及在建立队列、暴露评估、获取生物样品、核提取、选择适当的微阵列技术以及解释结果的分析工作方面的实用技能。这将通过正式课程来完成，这些课程是对候选人完成公共卫生硕士学位之前课程的补充，现场工作和合作工作，以学习如何测量环境内毒素暴露，以及如何招募、同意和维持队列，使用分子方法进行基准工作，出席机构和国家会议，以及来自现有导师和具有相关专业知识的多学科咨询委员会的指导。这将导致实践技能和科学知识的独特结合，帮助她实现独立于她的指导团队，并为实现她的长期职业目标做好准备。环境申请人将在世界著名的主要学术机构进行研究、培训和职业发展活动。她将工作的部门拥有一个合作环境，既有丰富的研究环境，又有强烈的临床重点，并在肺部和重症监护医学方面拥有卓越的导师、领导力和临床卓越的历史。她的机构对申请者的成功职业发展非常投入，并将为她的职业发展和拟议的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童哮喘以及环境和分子流行病学方面的专家，并将提供全面的资源，伴随着两个独特的内毒素暴露儿童和成人队列。

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.