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

项目总结/摘要 提案摘要 这是劳里埃尔德雷奇重新提交的NIH指导临床科学家职业发展奖， 医学博士，博士，华盛顿大学和西雅图儿童医院的助理教授。博士 埃尔德雷奇是建立自己作为在基础和转化研究的调查员集中在先天 新生儿肺损伤免疫反应这一建议建立在她的基础科学背景，包括 发展免疫学和她在转化研究方面的成长经验。这项建议的重点是 探讨细胞因子IL-33在支气管肺发育不良（BPD）中的作用。埃尔德雷奇医生 为这一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： 史蒂文·F.齐格勒博士（共同导师，疾病状态免疫机制的基础科学家），Jason S. Debley，医学博士，M.P.H.（共同导师，儿科肺病学家和哮喘转化研究者），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），桑德拉E。 Juul，医学博士，博士（共同导师，新生儿脑损伤的病理学家和转化研究员），邦妮W。 Ramsey，医学博士（咨询委员会、儿科肺病学家和囊性肺疾病的临床/转化研究人员） 纤维化）和Y. S.普拉卡什医学博士博士(BPD翻译研究专家和外部导师）。这 一个多学科小组设在贝纳罗亚研究所，西雅图儿童医院和研究 研究所、华盛顿大学和马约诊所。 研究计划： 本项目旨在研究细胞因子IL-33在新生儿肺损伤中的新作用。埃尔德雷奇医生会 使用高氧的独特组合来模拟小鼠中的BPD和来自人BPD的气道样本 患者完成以下具体目标： 目标1.确定单核/巨噬细胞和上皮细胞特异性IL-33信号转导在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 发病机制 这些研究将产生关于IL-33/ST 2信号传导作为一种新的炎症途径的重要信息。 波士顿警局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 影响新生儿对高氧肺损伤的免疫反应。这些研究还将确定IL- 33、其受体ST 2或下游生长因子双调蛋白可能是重要的BPD生物标志物， IL-33信号的调节是否可能是这些脆弱婴儿的未来疗法。这种平移 研究将成为NIH R 01申请和成功过渡到科学独立的基础 在K 08五年奖结束时。

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.