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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要提案摘要这是为 Laurie Eldredge 重新提交的 NIH 指导临床科学家职业发展奖，医学博士、哲学博士、华盛顿大学和西雅图儿童医院助理教授。埃尔德雷奇正在将自己定位为专注于先天性基础和转化研究的研究者该提案建立在她的基础科学背景基础上，包括新生儿肺损伤的免疫反应。该提案的重点是发育免疫学和她在转化研究方面不断增长的经验。 Eldredge 博士研究细胞因子 IL-33 在支气管肺发育不良 (BPD) 中的作用。为这个职业发展的关键时期组建了一个导师团队，由以下专家组成： Steven F. Ziegler，博士（共同导师，疾病状态免疫机制基础科学家），Jason S. Debley, M.D., M.P.H.（共同导师、儿科肺科医生和哮喘转化研究员），Charles W. Frevert，D.V.M.，ScD（顾问委员会、兽医病理学家和肺损伤基础科学家），Sandra E. Juul，医学博士、博士（新生儿脑损伤领域的联合导师、新生儿学家和转化研究员），Bonnie W. Ramsey，医学博士（Cystic 咨询委员会、儿科肺科医生和临床/转化研究员纤维化）和 Y.S. Prakash，医学博士、博士（BPD 转化研究专家和外部导师）。多学科团队位于贝纳罗亚研究所、西雅图儿童医院和研究中心研究所、华盛顿大学和梅奥诊所。研究计划：该项目旨在研究细胞因子 IL-33 在新生儿肺损伤中的新作用。使用高氧的独特组合来模拟小鼠 BPD 的演变以及人类 BPD 的气道样本患者完成以下具体目标：目标 1. 确定单核细胞/巨噬细胞和上皮细胞特异性 IL-33 信号传导在 HILI 中的作用。目标 2. 确定单核细胞和/或上皮细胞来源的 IL-33 信号传导是否有助于 BPD 发病。这些研究将提供有关 IL-33/ST2 信号传导作为一种新型炎症途径的重要信息。 BPD。结果将确定单核细胞/巨噬细胞和上皮细胞中的 IL-33 信号传导和串扰。这些研究还将确定 IL- 是否会影响新生儿对高氧引起的肺损伤的免疫反应。 33，其受体 ST2 或下游生长因子双调蛋白可能是重要的 BPD 生物标志物，并且 IL-33 信号传导的调节是否可能成为这些脆弱婴儿的未来疗法。研究将构成 NIH R01 申请和成功过渡到科学独立的基础到五年期K08奖结束时。