The unique role of IkBa in modulating NF-kB activity in the newborn lung.

描述(由申请者提供)：本建议书描述了为发展分子生物学和新生儿学的学术生涯而进行的为期5年的培训计划。这位候选人是费城儿童医院(CHOP)儿科科学家发展计划和新生儿科奖学金的最后一年。这项计划将扩大高氧性新生儿肺损伤的分子生物学方面的工作。菲利斯·丹纳利医学博士是氧化应激中新生儿肺基因调控领域的公认领导者，也是CHOP和宾夕法尼亚大学的儿科学教授，他将监督培训计划。该项目将由迈克尔·比尔斯医学博士共同指导，迈克尔·比尔斯是宾夕法尼亚大学肺损伤方面的权威人士和医学教授。为了加强培训，一个由在学术医学、肺损伤和核因子-kB信号转导方面具有专业知识的杰出科学家组成的咨询委员会已被征召来提供建议和指导。教师专业发展研讨会和授课课程将增强该计划的教育内容。CHOP和宾夕法尼亚大学的新生儿科和儿科系提供了独特的资源、核心设施、智力专长和潜在的合作伙伴来支持年轻教师。这是一个理想的培训环境，可以过渡到独立的学术生涯，成为一名内科科学家。在早产儿中，支气管肺发育不良(BPD)是常见的，并导致显著的长期发病率。临床研究表明，核因子-kB的激活与BPD发病风险的增加有关。高氧诱导新生小鼠肺组织中核因子-kB的活化。然而，导致这种激活和下游效应的机制途径尚不清楚。这一建议的中心假设是，IkB1是一种核因子-kB抑制蛋白，具有独特的特性，使其对于调节高氧诱导的新生肺中核因子-kB的激活至关重要。其具体目的包括：1)明确IkB1在胚胎和新生小鼠肺中的发育表达谱；2)检测IkB1特异性的非典型核因子-kB激活途径在高氧暴露的新生小鼠肺损伤中的作用；3)确定一氧化氮是否抑制了非典型的核因子-kB激活途径。通过进一步明确IkB1的独特特性及其在调节高氧诱导的NF-kB激活中的作用，我们希望确定针对早产儿预防BPD的干预措施。

DESCRIPTION (provided by applicant): This proposal describes the 5-year training program for the development of an academic career in molecular biology and Neonatology. The candidate is in his final year of the Pediatric Scientist Development Program and Neonatology fellowship at the Children's Hospital of Philadelphia (CHOP). This program will expand a body of work in the molecular biology of hyperoxic neonatal lung injury. Phyllis Dennery, MD, a recognized leader in the field of neonatal pulmonary gene regulation in oxidative stress and Professor of Pediatrics at CHOP and the University of Pennsylvania, will supervise the training program. The program will be co-mentored by Michael Beers, MD, an established authority on lung injury and Professor of Medicine at the University of Pennsylvania. To enhance training, an advisory committee consisting of distinguished scientists with expertise in academic medicine, lung injury and NF-kB signaling has been enlisted to provide advice and guidance. Faculty professional development seminars and didactic courses will enhance the educational content of the program. The Division of Neonatology and Department of Pediatrics of CHOP and University of Pennsylvania provide a unique combination of resources, core facilities, intellectual expertise and potential collaborations to support young faculty. This is an ideal training environment to transition to an independent academic career as a physician-scientist. In preterm infants, bronchopulmonary dysplasia (BPD) is common and leads to significant long-term morbidity. Clinical studies have correlated NF-kB activation to an increased risk of developing BPD. Hyperoxia induces NF-kB activation in the neonatal mouse lung. However, the mechanistic pathway leading to this activation and downstream effects are unknown. The central hypothesis of this proposal is that IkB1, a NF-kB inhibitory protein, has unique characteristics that make it essential for regulating hyperoxia-induced NF-kB activation in the newborn lung. The specific aims include: 1) Defining the developmental expression profile of IkB1 in the fetal and neonatal mouse lung, 2) Testing the role of the IkB1 specific atypical pathway of NF-kB activation in modulating lung injury in neonatal mice exposed to hyperoxia, and 3) Determining whether nitric oxide inhibits the atypical pathway of NF-KB activation. By further defining the unique characteristics of IkB1 and its role in modulating hyperoxia-induced NF-kB activation, we hope to identify interventions targeted at protecting preterm infants from BPD.