The role of IL-33 in hyperoxia-induced neonatal lung injury and bronchopulmonary dysplasia

IL-33在高氧诱导的新生儿肺损伤和支气管肺发育不良中的作用

• 批准号: 10593394
• 负责人: LAURIE CHRISTINE ELDREDGE
• 金额: $ 16.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593394
• 关键词: Acute; Advisory Committees; Affect; Alveolar; Amphiregulin; Anti-Inflammatory Agents; Aspirate substance; Asthma; Automobile Driving; Award; Basic Science; Biological Markers; Blood; Bronchopulmonary Dysplasia; Caring; Cell Communication; Cells; Child; Childhood; Chronic; Chronic lung disease; Clinic; Clinical; Coculture Techniques; Complement; Cystic Fibrosis; Data; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Doctor of Veterinary Medicine; Dominant-Negative Mutation; Down-Regulation; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Exposure to; Future; Goals; Growth Factor; Histologic; Human; Hyperoxia; ITGAM gene; Immune; Immune response; Immunity; Immunobiology; Immunologics; Infant; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; JUUL; K-Series Research Career Programs; Life; Lung; Lung diseases; Master of Public Health; Mediating; Medicine; Mentors; Messenger RNA; Modeling; Molecular Target; Mus; Mutant Strains Mice; Neonatal; Neonatal Brain Injury; Newborn Infant; Oxygen; Pathogenesis; Pathogenicity; Pathologist; Pathway interactions; Patients; Pediatric Hospitals; Physiological; Premature Infant; Research; Research Institute; Research Personnel; Risk; Role; Sampling; Scientist; Severities; Signal Transduction; Source; Testing; Translational Research; United States; United States National Institutes of Health; Universities; Washington; Wild Type Mouse; Work; base; career development; cell injury; comparative; conditional mutant; critical period; cytokine; developmental immunology; experience; experimental study; field study; hyperoxia induced lung injury; immunoregulation; improved; in utero; lung injury; macrophage; monocyte; mortality; mouse model; multidisciplinary; neonatal immune system; neonatal lung injury; neonatal mice; novel; paracrine; peripheral blood; potential biomarker; professor; prospective; receptor; repaired; response; supplemental oxygen; transcriptome sequencing; translational scientist

PROJECT SUMMARY/ABSTRACT Summary of Proposal This is resubmission for an NIH Mentored Clinical Scientist Career Development Award for Laurie Eldredge, M.D., Ph.D., an Assistant Professor at the University of Washington and Seattle Children’s Hospital. Dr. Eldredge is establishing herself as in investigator in basic and translational research focused on the innate immune response in neonatal lung injury. This proposal builds upon her background in basic science including developmental immunology and her growing experience in translational research. The focus of this proposal is to investigate the role for the cytokine IL-33 in bronchopulmonary dysplasia (BPD). Dr. Eldredge has assembled a team of mentors for this critical period of career development, comprised of the following experts: Steven F. Ziegler, Ph.D. (co-mentor, basic scientist in immunological mechanisms of disease states), Jason S. Debley, M.D., M.P.H. (co-mentor, pediatric pulmonologist and translational researcher in asthma), Charles W. Frevert, D.V.M., ScD (advisory committee, veterinary pathologist and basic scientist in lung injury), Sandra E. Juul, M.D., Ph.D. (co-mentor, neonatologist and translational researcher in neonatal brain injury), Bonnie W. Ramsey, M.D. (advisory committee, pediatric pulmonologist and clinical/ translational researcher in Cystic Fibrosis), and Y.S. Prakash, M.D., Ph.D. (BPD translational research expert and external mentor). This multidisciplinary team is based at Benaroya Research Institute, Seattle Children’s Hospital and Research Institute, the University of Washington, and Mayo Clinic. Research Plan: This project proposes to investigate a novel role for the cytokine IL-33 in neonatal lung injury. Dr. Eldredge will use a unique combination of hyperoxia to model evolving BPD in mice and airway samples from human BPD patients to complete the following specific aims: Aim 1. Determine the rolesof monocyte/macrophage and epithelial cell specific IL-33 signaling in HILI. Aim 2. Determine whether monocyte and/or epithelial cell-derived IL-33 signaling contributes to BPD pathogenesis. These studies will yield important information about IL-33/ST2 signaling as a novel inflammatory pathway in BPD. Results will determine how IL-33 signaling and crosstalk in monocytes/macrophages and epithelial cells affect the neonatal immune response to hyperoxia-induced lung injury. These studies will also determine if IL- 33, its receptor ST2, or the downstream growth factor amphiregulin may be important BPD biomarkers, and whether modulation of IL-33 signaling may be a future therapy for these fragile infants. This translational research will form the basis for an NIH R01 application and a successful transition to scientific independence by the end of the five-year K08 award.

项目摘要/摘要 建议书摘要 这是为劳里·埃尔德里奇重新提交的NIH临床科学家指导职业发展奖， 医学博士，华盛顿大学和西雅图儿童医院助理教授。Dr。 埃尔德里奇在基础研究和翻译研究中确立了自己的地位，专注于先天的 新生儿肺损伤的免疫反应。这项提议建立在她的基础科学背景之上，包括 发展免疫学和她在翻译研究方面不断增长的经验。这项提案的重点是 探讨细胞因子IL-33在支气管肺发育不良(BPD)中的作用。埃尔德里奇博士已经 为这一职业发展的关键时期组建了一支导师团队，由以下专家组成： 史蒂文·F·齐格勒博士(共同导师，疾病状态免疫学机制的基础科学家)，Jason S。 Debley，M.D.，M.P.H.(哮喘方面的共同导师、儿科肺病学家和翻译研究员)，Charles W. Frevert，D.V.M.，ScD(咨询委员会，兽医病理学家和肺损伤基础科学家)，Sandra E. Juul，M.D.，Ph.D.(新生儿脑损伤的共同导师、新生儿科专家和翻译研究员)，Bonnie W. Ramsey医学博士(咨询委员会、儿科肺病专家和囊性疾病临床/翻译研究人员 纤维化)，Y.S.Prakash，医学博士，博士(BPD转化研究专家和外部导师)。这 多学科团队驻扎在西雅图儿童医院贝纳罗亚研究所和研究 华盛顿大学和梅奥诊所。 研究计划： 本项目旨在探讨细胞因子IL-33在新生儿肺损伤中的新作用。埃尔德里奇医生会 使用一种独特的高氧组合来模拟小鼠BPD的演变和人类BPD的呼吸道样本 患者要完成以下具体目标： 目的1.探讨单核/巨噬细胞和上皮细胞特异性IL-33信号在HALI中的作用。 目的2.确定单核细胞和/或上皮细胞来源的IL-33信号是否与BPD有关 发病机制。 这些研究将提供有关IL-33/ST2信号通路作为一种新的炎症途径的重要信息。 每桶。结果将确定IL-33信号和单核/巨噬细胞和上皮细胞中的串扰 影响新生儿对高氧性肺损伤的免疫反应。这些研究还将确定IL-1是否 33、其受体ST2或下游的生长因子双调节蛋白可能是BPD的重要生物标志物。 调节IL-33信号是否可能成为这些脆弱婴儿的未来治疗方法。此翻译 研究将为NIH R01的应用和成功过渡到科学独立奠定基础 到五年K08奖项结束时。