EPITHELIAL IL-33 IN THE PATHOGENESIS OF CHRONIC AIRWAY DISEASE

上皮 IL-33 在慢性气道疾病发病机制中的作用

基本信息

批准号：
8829331
负责人：
Jennifer Alexander-Brett
金额：
$ 11.42万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8829331
关键词：
Address Advisory Committees Antibodies Asthma Attenuated Basal Cell Basic Science Biological Assay Biology Bone Marrow Cause of Death Cell Differentiation process Cell physiology Cells Cellular Stress Chimera organism Chimeric Proteins Chronic Chronic Obstructive Airway Disease Confocal Microscopy Critical Care Cytolysis Data Development Plans Disease Disease model Doctor of Philosophy Enzyme-Linked Immunosorbent Assay Epithelial Epithelial Cells Feedback Future Genes Goals Health Human Immune In Vitro Inflammation Inflammatory Interferometry Interleukin-13 Internal Medicine International Investigation LacZ Genes Life Lung Lung diseases Manuscripts Mass Spectrum Analysis Measures Mediating Mediator of activation protein Medicine Mentors Metaplasia Modeling Molecular Morbidity - disease rate Mucous body substance Mus Myeloid Cells N-terminal Nature Organelles Pathogenesis Pathologic Pathway interactions Patients Phase Physicians Physiology Population Preparation Process Production Proteins Public Health Publications Reagent Receptor Signaling Recombinants Recording of previous events Reporter Research Research Personnel Research Training Role Sampling Scientist Sendai virus Signal Transduction Source Staging Stem cells Stimulus Stromal Cells Supervision System Testing Therapeutic Therapeutic Intervention TimeLine Tissue Sample Tracheobronchial Training United States Universities Vesicle Viral Virus Diseases Washington Western Blotting Work airway mucous cell metaplasia airway obstruction base career career development cellular targeting cytokine design disease phenotype effective therapy immune activation in vitro activity in vivo inflammatory lung disease inhibitor/antagonist medical schools monocyte mortality mouse model novel parainfluenza virus progenitor receptor respiratory infection virus respiratory virus structural biology targeted treatment tool trafficking

项目摘要

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.

描述（由申请人提供）：该提案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 Jennifer Alexander-Brett 博士转变为独立学术研究员。她拥有深厚的基础科学研究和医学背景，并完成了内科和肺/重症监护医学的研究生培训。该提案的主要目标是为 Alexander-Brett 博士提供必要的框架和支持，以实现她作为一名医生科学家的职业目标，过渡到肺部疾病的独立科学研究。这项工作将进行在 Michael J. Holtzman 博士的指导下，在华盛顿大学医学院进行研究。华盛顿大学以其悠久的研究历史而闻名。同样，霍尔茨曼博士是肺生物学领域的国际领导者，专注于慢性阻塞性肺疾病（如慢性阻塞性肺病和哮喘）的机制，并拥有非常成功的指导记录。具有多元化专业知识的咨询委员会将提供职业指导和科学反馈。提出了详细的职业发展计划，其中包括定期参加学术活动、科学演讲、准备出版手稿的时间表以及最终的 R01 申请以实现独立。拟议的研究计划将侧重于慢性气道疾病的机制研究，长期目标是确定适合治疗干预的途径。这项工作的初始训练阶段利用了导师实验室开发和验证的副流感病毒诱导的慢性气道疾病小鼠模型，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。具体来说，该提案将解决上皮衍生细胞因子 IL-33 作为先天免疫激活和随之而来的粘液过量产生的驱动因素的功能。该项目的初步工作表明，慢性气道疾病依赖于小鼠模型中的 IL-33-IL-33R 信号，并且该信号在患有慢性阻塞性肺病（COPD）引起的类似疾病的人类中也被激活。然而，上皮 IL-33 在气道疾病中发挥作用的分子机制在很大程度上仍不明确，因此将通过三个具体目标来实现：目标 1 将解决小鼠模型中 IL-33 活性的细胞来源和效应子。目标 2 将重点关注表达 IL-33 的上皮细胞作为祖细胞群的功能特征，该细胞群可能使气道分化偏向粘液过量产生。目标 3 针对上皮细胞中 IL-33 激活和释放的细胞生物学和最终结构生物学。总之，这些目标将解决导致慢性气道疾病的上皮-先天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病关键细胞因子系统的高水平研究生涯。