The Role of TLR4 in Environmental Asthma

描述(由申请人提供) 此应用程序的目标是支持John博士的职业发展 这样，在完成颁奖时，他将是一个独立的 研究人员和杰出的学术临床医生-科学家在 环境呼吸道疾病。大卫·施瓦茨博士将承担责任 作为导师，确保职业发展计划的成功。这个 这项建议的基础是广泛的指导性研究培训 环境哮喘遗传流行病学研究经验。培训 过程将包括临床研究方法学的教学课程工作， 遗传学和遗传流行病学；Marcy Speer博士在遗传学方面的指导 分析方法；以及完成一项研究项目。施瓦茨博士将 监督桑迪博士完成一项研究项目，其目的是 慢性阻塞性肺疾病患者对内毒素免疫应答的缺陷 脂多糖受体Toll样受体4(TLR4)基因突变。LP 是谷物粉尘和其他环境生物气溶胶的重要组成部分 会引起呼吸道炎症和气流阻塞；被认为是 在环境性哮喘的发病机制中具有重要作用。候选人的 实验室表明，TLR4中常见的共分离突变是 与吸入内毒素引起的呼吸道反应性降低有关。一个重要的 悬而未决的问题是TLR4的突变是否会影响内毒素诱导的免疫 在人类中的反应，如果是这样的话，这些免疫变化是否是 TLR4突变个体内毒素反应性的生理变化。 他们假设Asp299GIy和Asp299GIy共分离的个体 TLR4基因Thr3991le突变将显示免疫反应缺陷 以及这些人体内免疫变化的特定成分 与对内毒素的特殊呼吸道反应有关。为了测试这一点 假设，桑迪博士将识别健康的、非哮喘的人 共分离Asp299GIy和Thr399Ile TLR4突变或个体 是TLR4的野生型，并比较它们在体外和体内对内毒素的反应 挑战。将内毒素诱导的免疫反应与内毒素诱导的免疫反应进行比较 气流障碍的变化以确定潜在的联系机制 对生理学免疫。这些研究将有助于通过以下方式确定机制 其中一个重要的基因-环境相互作用(TLR4和内毒素) 在环境性哮喘的发病机制中起着重要作用。桑迪博士会 在施瓦茨和施佩尔博士的指导下进行这些研究。他会的 有权使用杜克大学的资源，包括人类遗传学中心， 杜克临床研究所和综合临床研究中心 来执行他的职业发展计划。导师和机构都是 高度致力于桑迪博士的职业发展和学术成功。

DESCRIPTION (provided by applicant) The goal of this application is to support the career development of Dr. John Sundy so that at the completion of the award he will be an independent researcher and outstanding academic clinician-scientist in the field of environmental airway disease. Dr. David Schwartz will assume responsibility as mentor to ensure the success of the career development plan. The foundation of this proposal is an extensive mentored research training experience in the genetic epidemiology of environmental asthma. The training process will comprise didactic course work in clinical research methodology, genetics and genetic epidemiology; mentoring by Dr. Marcy Speer in genetic analysis methods; and completion of a research project. Dr. Schwartz will supervise Dr. Sundy in completing a research project aimed at characterizing defects in immune responses to lipopolysaccharide (LPS) in individuals with mutations in the gene for Toll-like receptor 4 (TLR4), an LPS receptor. LPS is an important component of grain dusts and other environmental bioaerosols that cause airway inflammation and airflow obstruction; and is thought to be important in the pathogenesis of environmental asthma. The candidate's laboratory has shown that common cosegregating mutations in TLR4 are associated with reduced airway responsiveness to inhaled LPS. An important unanswered question is whether mutations in TLR4 affect LPS induced immune responses in humans and, if so, whether these changes in immunity underlie the physiologic alterations in LPS responsiveness among TLR4 mutant individuals. They hypothesize that individuals with the co-segregating Asp299GIy and Thr3991le mutations in the TLR4 gene will exhibit a defective immune response to LPS, and that specific components of altered immunity in these individuals are linked to characteristic airway responses to LPS. To test this hypothesis, Dr. Sundy will identify healthy, non-asthmatic individuals with the co-segregating Asp299GIy and Thr399Ile TLR4 mutations or individuals who are wild type for TLR4, and compare their response to in vitro and in vivo LPS challenge. LPS-induced immune responses will be compared to LPS-induced changes in airflow obstruction to identify potential mechanisms linking immunity to physiology. These studies will help determine the mechanisms by which an important gene-environment interaction (TLR4 and endotoxin) contributes to the pathogenesis of environmental asthma. Dr. Sundy will perform these studies with the mentoring of Drs. Schwartz and Speer. He will have access to the resources of Duke, including the Center for Human Genetics, the Duke Clinical Research Institute, and the General Clinical Research Center to carry out his career development plan. Both the mentor and the institution are highly committed to Dr. Sundy's career development and academic success.