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

IkBa 在调节新生肺中 NF-kB 活性方面​​的独特作用。

• 批准号: 8652491
• 负责人: Clyde Jason Wright
• 金额: $ 13.39万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652491
• 关键词: Accounting; Advisory Committees; Affect; Apoptosis; Architecture; Beer; Binding; Birth; Bronchopulmonary Dysplasia; Cell Adhesion Molecules; Cell Culture Techniques; Cell Survival; Cells; Characteristics; Childhood; Chronic lung disease; Clinical; Clinical Research; Clinical Trials; Collaborations; Complementary DNA; Core Facility; Cytoplasm; DNA Binding; Data; Defect; Development; Disease; Drug Metabolic Detoxication; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Environment; Exhibits; Exposure to; Faculty; Family; Family member; Fellowship; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Hyperoxia; Immunohistochemistry; Infant; Inflammation; Inflammatory; Injury; Intervention; Knock-in Mouse; Lasers; Low Birth Weight Infant; Lung; Medicine; Mentors; Messenger RNA; Microdissection; Modeling; Molecular; Molecular Biology; Molecular Profiling; Morbidity - disease rate; Mus; Mutant Strains Mice; N-terminal; NF-kappa B; Neonatal; Neonatology; Newborn Animals; Newborn Infant; Nitric Oxide; Nuclear Translocation; Oxidants; Oxidative Stress; Partner in relationship; Pathway interactions; Pattern; Pediatric Hospitals; Pediatrics; Pennsylvania; Perinatal; Philadelphia; Phosphorylation; Physicians; Post-Translational Protein Processing; Pregnancy; Premature Birth; Premature Infant; Program Development; Proteins; Public Health; Relative (related person); Repression; Resources; Risk; Role; Sampling; Scientist; Serine; Signal Pathway; Signal Transduction; Skin; Staging; Stress; Structure of parenchyma of lung; Testing; Time; Tissues; Training; Training Programs; Tyrosine; Universities; authority; biological adaptation to stress; career; dimer; fetal; in vivo; inhaled nitric oxide; insight; lung development; lung injury; member; neonatal lung injury; nitration; oxidant stress; pediatric department; postnatal; prevent; professor; programs; protein B; public health relevance; research study; response; transcription factor

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. PUBLIC HEALTH RELEVANCE: Project Narrative Preterm delivery affects more than 12% of all births and accounts for more than 85% of all perinatal complications. Premature delivery predisposes infants to the development of bronchopulmonary dysplasia, or chronic lung disease, and each year 10,000 to 15,000 newborns develop this disease. Interventions aimed at preventing the development of BPD will reduce the impact of this major public health burden.

描述（由申请人提供）：此提案描述了分子生物学和新生儿学学术生涯发展的5年培训计划。该候选人是费城儿童医院（CHOP）儿科科学家发展计划和新生儿学奖学金的最后一年。该计划将扩大在高氧新生儿肺损伤的分子生物学的工作体。新生儿肺部氧化应激基因调控领域公认的领导者、CHOP和宾夕法尼亚大学儿科学教授Phyllis Dennery医学博士将监督培训计划。该项目将由迈克尔·比尔斯医学博士共同指导，他是肺损伤领域的权威，也是宾夕法尼亚大学的医学教授。为了加强培训，一个由在学术医学、肺损伤和NF-kB信号方面具有专长的杰出科学家组成的咨询委员会已被征募，以提供咨询和指导。教师专业发展研讨会和教学课程将加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提供了独特的资源组合，核心设施，知识专长和潜在的合作，以支持年轻教师。这是一个理想的培训环境，过渡到一个独立的学术生涯作为一个医生-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NF-kB活化与BPD发病风险增加有关。高氧诱导新生小鼠肺NF-kB活化。然而，导致这种激活的机制途径和下游效应尚不清楚。该建议的中心假设是，IkB1是一种NF-kB抑制蛋白，具有独特的特性，使其对调节新生儿肺部高氧诱导的NF-kB激活至关重要。具体目的包括：1)确定IkB1在胎儿和新生小鼠肺中的发育表达谱；2)检测IkB1特异性NF-kB激活非典型途径在高氧新生小鼠肺损伤中的调节作用；3)确定一氧化氮是否抑制NF-kB激活的非典型途径。通过进一步确定IkB1的独特特征及其在调节高氧诱导的NF-kB激活中的作用，我们希望确定针对保护早产儿免受BPD的干预措施。

项目成果

Abdominal radiograph with intravesical air and possible small bowel atresia.

腹部 X 光片显示膀胱内空气，可能有小肠闭锁。

• DOI: 10.1016/j.jpeds.2013.12.017
• 发表时间: 2014
• 期刊: The Journal of pediatrics
• 作者: Stewart,MichaelS;Dietz,RobertM;Landman,MatthewP;Moulton,StevenL;Wright,ClydeJ
• 通讯作者: Wright,ClydeJ

Endotoxemia Induces IκBβ/NF-κB-Dependent Endothelin-1 Expression in Hepatic Macrophages.

• DOI: 10.4049/jimmunol.1501017
• 发表时间: 2015-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: McKenna S;Gossling M;Bugarini A;Hill E;Anderson AL;Rancourt RC;Balasubramaniyan N;El Kasmi KC;Wright CJ
• 通讯作者: Wright CJ

Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism.

• DOI: 10.1159/000445541
• 发表时间: 2016
• 期刊: Journal of innate immunity
• 影响因子: 5.3
• 作者: McKenna S;Eckman M;Parker A;Bok R;Hurt KJ;Wright CJ
• 通讯作者: Wright CJ