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

• 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
• 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

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）：本提案描述了一个为期五年的研究和培训计划，将促进詹妮弗亚历山大-布雷特博士，医学博士，博士过渡到一个独立的学术研究人员。她在基础科学研究和医学方面有很强的背景，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，过渡到对肺部疾病的独立科学研究。 这项工作将由 在华盛顿大学医学院的迈克尔·J·霍尔茨曼博士的监督下。华盛顿大学以其强大的研究历史而闻名。同样，Holtzman博士是肺生物学的国际领导者，专注于慢性阻塞性肺疾病（如COPD和哮喘）的机制，并拥有非常成功的指导记录。一个具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。提出了一个详细的职业发展计划，将包括定期参加学术活动，科学报告，和时间轴的手稿准备出版和最终的R 01应用程序的独立的道路。 拟议的研究计划将侧重于慢性气道疾病的机制研究，其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在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。具体地，该提议将解决上皮来源的细胞因子IL-33作为先天免疫激活和随后的粘液过度产生的驱动器的功能。该项目的初步工作已经证明，慢性气道疾病依赖于小鼠模型中的IL-33-IL-33 R信号，并且该信号也在患有COPD所致类似疾病的人类中被激活。然而，气道疾病中上皮IL-33功能的分子机制在很大程度上仍不明确，因此将通过三个特定目标来解决：目标1将解决小鼠模型中IL-33活性的细胞来源和效应物。目的2将集中于表达IL-33的上皮细胞作为可能使气道分化向粘液过度产生倾斜的祖细胞群的功能特征。目的3靶向上皮细胞中IL-33激活和释放的细胞生物学和最终结构生物学。总之，这些目标将解决驱动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博士能够发展高水平的研究事业，专注于调节炎症性肺病中的关键细胞因子系统。