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: 9266466
• 负责人: Jennifer Alexander-Brett
• 金额: $ 15.62万
• 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/9266466
• 关键词: Address; Advisory Committees; Antibodies; Asthma; Attenuated; Basal Cell; Basic Science; Biochemical; 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; Human; Immune; In Vitro; Inflammation; Inflammatory; Interferometry; Interleukin-13; Internal Medicine; International; Investigation; LacZ Genes; 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; Pathogenicity; 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; Stem cells; Stimulus; Stromal Cells; Supervision; System; TNFSF5 gene; Testing; Therapeutic; Therapeutic Intervention; TimeLine; Tissue Sample; Tracheobronchial; Training; United States; Universities; Vesicle; Viral; Virus Diseases; Vocational Guidance; 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; public health relevance; 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）：该提案描述了一个五年的研究和培训计划，该计划将促进Jennifer Alexander-Brett博士从医学博士到独立学术研究员的过渡。她在基础科学研究和医学方面有很强的背景，并完成了内科和肺部/重症医学的研究生培训。该提案的主要目标是为Alexander-Brett博士提供必要的框架和支持，以实现她作为医生科学家的职业目标，过渡到肺病的独立科学研究。这项工作将进行下去