The role of chorioamnionitis-induced perinatal alterations of Heme-oxygenase-1 (HO-1) pathway on neuroinflammation and neonatal white matter injury

项目摘要/摘要： 申请书中的建议概述了一项为期五年的培训计划，以发展作为一名 新生儿神经免疫学内科医生兼科学家。候选人迈德·奥岑博士是一名早期研究员， 约翰霍普金斯大学医学院儿科学助理教授。拟议的研究 将在翻译专家Lauren L.Jantzie博士的主要指导下进行 围产期脑损伤的调查分析候选人S的共同导师是谢南多·罗宾逊博士，医学博士，专家 少突胶质细胞生物学和弗朗西斯·J·诺辛顿博士，医学博士，受人尊敬的新生儿学家和细胞学的领导者 大脑中的死亡路径。本次K08提案的具体培训目标是：发展Ozen博士的科学 和专业技能1)高级神经免疫学和神经科学技术，2)基因-蛋白质 血红素加氧酶-1(HO-1)特有的相互作用，为未来R01的应用奠定基础。 JHU的神经科学研究异常强大。奥岑博士和她的指导委员会已经开发出 有针对性地实现这些目标。体验式研究环境，智力指导 精心挑选的教学课程，每一门都与这项提案中的特定目标相匹配，将确保严格 神经免疫学方面的训练，以达到独立。 脑白质损伤(WMI)是早产儿最常见的脑损伤形式。主要关注点 候选人提出的项目是首次在围产期WMI中询问HO-1途径。HO-1是一种抗-1 炎症、抗凋亡和细胞保护酶在免疫调节和IS中起重要作用 表达于单核细胞、小胶质细胞和少突胶质细胞。这位候选人是第一个证明这一点的 绒毛膜羊膜炎围生期大鼠脑内HO-1通路的改变与 神经炎。因此，利用经过验证的脑瘫绒毛膜模型，候选人将首先 确定绒毛膜如何改变WMI中的HO-1途径；第二，确定细胞内HO-1在WMI中的表达 外周血单个核细胞和脑小胶质细胞对绒毛膜早破WMI有不同的影响；第三，确定 HO-1通路的调节对绒毛膜上皮细胞WMI具有保护作用。完成有针对性的职业发展 此建议书中提出的计划和研究将使应聘者能够学习新的技术技能并获得 神经科学专业知识在神经免疫学领域脱颖而出，推动HO-1领域的发展 生物学对围产期脑损伤的影响。对绒毛膜HO-1途径调控的严格研究可以提供 围产期免疫介导的WMI的新生物标志物和靶向治疗策略的发现。

PROJECT SUMMARY/ABSTRACT: The proposal in this application outlines a five-year training program for the development of a career as a physician-scientist in neonatal neuroimmunology. Candidate, Dr. Maide Ozen, is an Early Stage Investigator and an Assistant Professor of Pediatrics at the Johns Hopkins University School of Medicine. The proposed research will be carried out under the primary mentorship of Dr. Lauren L. Jantzie, PhD, an expert leader in translational investigations in perinatal brain injury. Candidate’ s co-mentors are Dr. Shenandoah Robinson, M.D. an expert in oligodendrocyte biology and Dr. Frances J. Northington, M.D. an esteemed Neonatologist and a leader in cell death pathways in the brain. Specific training objectives of this K08 proposal are: develop Dr. Ozen’s scientific and professional skills in 1) advanced neuroimmunology and neuroscience techniques, 2) gene-protein interactions specific to Heme oxygenase-1 (HO-1) to lay the foundation for a future R01 application. Neuroscience research at JHU is exceptionally strong. Dr. Ozen and her mentoring committee have developed a focused approach to achieve these objectives. The experiential research environment, intellectual guidance and carefully selected didactic courses, each matched to a specific aim in this proposal, will ensure rigorous training in neuroimmunology for achieving independence. White matter injury (WMI) is the most common form of brain injury in preterm neonates. Key focus of candidates proposed project is interrogating HO-1 pathway, for the first time, in perinatal WMI. HO-1 is an anti- inflammatory, anti-apoptotic and cytoprotective enzyme with essential roles in immune regulation and is expressed in mononuclear cells, microglia and oligodendrocytes. The candidate is the first to show that chorioamnionitis-induced perinatal alterations of HO-1 pathway in the developing rat brain correlate with neuroinflammation. Therefore, utilizing a validated CHORIO model of Cerebral Palsy, the candidate will first determine how CHORIO alters HO-1 pathway in WMI; second, determine if intracellular HO-1 expression in peripheral mononuclear cells and brain microglia differentially contribute to WMI in CHORIO; third, determine if modulation of HO-1 pathway will protect from WMI in CHORIO. Completion of the targeted career development program and research proposed in this proposal will allow the candidate to learn new technical skills and gain neuroscience expertise to excel as a physician-scientist in neuroimmunology and advance the field of HO-1 biology to perinatal brain injury. Rigorous inquiry in regulation of HO-1 pathway in CHORIO could provide discovery of novel biomarkers and targeted therapeutic strategies for perinatal immune-mediated WMI.