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约翰博士的职业发展 桑迪，以便在完成该奖项，他将是一个独立的 研究员和杰出的学术临床医生，科学家在该领域的 环境气道疾病。 大卫·施瓦兹医生将负责 作为导师，确保职业发展计划的成功。 的 这项建议的基础是一个广泛的指导研究培训 环境哮喘遗传流行病学经验。 培训 过程将包括临床研究方法学的教学课程， 遗传学和遗传流行病学;由Marcy Speer博士指导遗传学 分析方法;完成一个研究项目。 施瓦茨医生会 指导Sundy博士完成一项旨在描述 脂多糖（LPS）的免疫应答缺陷， Toll样受体4（TLR4）基因突变，一种LPS受体。 LPS 是谷物粉尘和其他环境生物气溶胶的重要组成部分 导致气道炎症和气流阻塞;被认为是 在环境性哮喘的发病机制中起重要作用。 候选人的 实验室已经表明，TLR4中常见的共分离突变是 与气道对吸入LPS的反应性降低有关。 一个重要 一个尚未回答的问题是TLR4突变是否影响LPS诱导的免疫反应 如果是这样，这些免疫力的变化是否是 TLR4突变个体中LPS反应性的生理改变。 他们假设具有Asp299Gly和Asp299Gly共分离基因的个体， TLR4基因中的Thr3991le突变将表现出免疫应答缺陷 LPS，以及这些个体中改变免疫力的特定成分 与气道对LPS的反应有关。 为了验证这一 假设，Sundy博士将识别健康，非哮喘个体， Asp299Gly和Thr399Ile TLR4突变的共分离个体或 是野生型TLR4，并比较它们对体外和体内LPS的反应 挑战. 将LPS诱导的免疫应答与LPS诱导的免疫应答进行比较。 气流阻塞的变化，以确定潜在的机制， 对生理学的免疫力 这些研究将有助于确定机制， 这是一个重要的基因-环境相互作用（TLR4和内毒素） 有助于环境性哮喘的发病机制。 桑迪博士会 在Schwartz和Speer博士的指导下进行这些研究。 他将 可以使用杜克的资源，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 来实现他的职业发展计划。 导师和机构 高度致力于Sundy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.