EPITHELIAL IL-33 IN THE PATHOGENESIS OF CHRONIC AIRWAY DISEASE

描述(由申请人提供)：本建议描述了一项为期五年的研究和培训计划，该计划将促进医学博士詹妮弗·亚历山大-布雷特向独立学术研究人员的过渡。她在基础科学研究和医学方面拥有深厚的背景，并已完成内科和肺部/危重护理医学的研究生培训。这项建议的主要目标是为Alexander-Brett博士提供必要的框架和支持，以通过过渡到肺部疾病的独立科学研究来实现她作为内科科学家的职业目标。这项工作将付诸实施 在华盛顿大学医学院，在迈克尔·J·霍尔茨曼博士的监督下。华盛顿大学以其雄厚的研究历史而闻名。同样，霍尔茨曼博士是肺部生物学的国际领导者，专注于慢性阻塞性肺疾病(COPD)和哮喘等慢性阻塞性肺疾病的发病机制，并在指导方面取得了非常成功的记录。一个拥有不同专业知识的咨询委员会将提供职业指导和科学反馈。提出了一项详细的职业发展计划，其中将包括定期参加学术活动、科学陈述、准备出版手稿的时间表以及最终在独立之路上申请R01。拟议的研究计划将重点放在慢性呼吸道疾病的机制研究上，长期目标是确定适合治疗干预的途径。这项工作的初始培训阶段利用了副流感病毒诱导的慢性呼吸道疾病小鼠模型，该模型是在导师的实验室开发和验证的，而后期阶段旨在发展候选人在结构生物学方面的独立研究。具体地说，这项建议将解决上皮源性细胞因子IL-33作为先天免疫激活和随之而来的粘液过度生产的驱动因素的功能。该项目的初步工作表明，慢性呼吸道疾病依赖于小鼠模型中的IL-33-IL-33R信号，该信号在患有类似COPD疾病的人类中也被激活。然而，上皮性IL-33在呼吸道疾病中作用的分子机制在很大程度上仍不明确，因此将以三个特定的目标来探讨：目标1将在小鼠模型中解决IL-33活性的细胞来源和效应因子。目的2将重点研究表达IL-33的上皮细胞作为前体细胞的功能特征，这可能会使气道分化向粘液过度生产倾斜。目的3针对上皮细胞中IL-33的激活和释放的细胞生物学和最终结构生物学。总而言之，这些目标将解决导致慢性呼吸道疾病的上皮-先天性免疫相互作用的病理序列中的关键步骤，并使Alexander-Brett博士能够发展专注于调节炎症性肺部疾病中的关键细胞因子系统的高水平研究生涯。

DESCRIPTION (provided by applicant): This proposal describes a five-year research and training plan that will facilitate the transition of Dr. Jennifer Alexander-Brett, MD PhD to an independent academic researcher. She has a strong background in basic science research and medicine and has completed post-graduate training in Internal Medicine and Pulmonary/Critical Care Medicine. The primary goal of this proposal is to provide the framework and support necessary for Dr. Alexander-Brett to fulfill her career goals as a physician-scientist through transition to independent scientific investigation in pulmonary disease. This work will be carried out at Washington University School of Medicine under the supervision of Dr. Michael J. Holtzman. Washington University is well known for its strong history of research. Likewise, Dr. Holtzman is an international leader in lung biology with a focus on mechanisms of chronic obstructive lung diseases such as COPD and asthma and a highly successful track record of mentoring. An advisory committee with diverse expertise will provide career guidance and scientific feedback. A detailed career development plan is proposed that will include regular participation in scholarly activities, scientific presentations, and a timeline for preparation of manuscripts for publication and an eventual R01 application in a pathway to independence. The proposed research plan will focus on mechanistic studies of chronic airway disease with the long-term goal of defining pathways amenable to therapeutic intervention. The initial training phase of this work takes advantage of a parainfluenza virus-induced mouse model of chronic airway disease that was developed and validated in the mentor's lab, while later stages are designed to develop the candidate's independent research in structural biology. Specifically, this proposal will address the function of epithelial- derived cytokine IL-33 as a driver of innate immune activation and consequent mucus overproduction. Initial work on this project has demonstrated that chronic airway disease depends on an IL-33-IL-33R signal in the mouse model, and this signal is also activated in humans with comparable disease due to COPD. However, the molecular mechanism of epithelial IL-33 function in airway disease remains largely undefined and will therefore be approached with three Specific Aims: Aim 1 will address the cellular sources and effectors of IL-33 activity in the mouse model. Aim 2 will focus on the functional characterization of IL-33-expressing epithelial cells as a progenitor population that potentially skews airway differentiation toward mucus overproduction. Aim 3 targets the cellular and eventually structural biology of IL-33 activation and release in epithelial cells. Together, these aims will address key steps in the pathologic sequence of epithelial-innate immune interactions that drive chronic airway disease, and allow Dr. Alexander-Brett to develop a high- level research career focused on regulating a key cytokine system in inflammatory lung disease.