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）：本提案描述了在分子生物学和新生儿学的学术生涯发展的5年培训计划。候选人是在他的儿科科学家发展计划和新生儿奖学金在费城儿童医院（CHOP）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机构。Phyllis登内里，医学博士，新生儿肺基因调控领域的公认领导者，CHOP和宾夕法尼亚大学的儿科教授，将监督培训计划。该计划将由Michael Beers博士共同指导，他是宾夕法尼亚大学肺损伤方面的权威和医学教授。为了加强培训，一个由在学术医学、肺损伤和NF-kB信号传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招募提供建议和指导。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系提供了独特的资源，核心设施，知识专长和潜在的合作组合，以支持年轻的教师。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，并导致显着的长期发病率。临床研究已经将NF-kB激活与发展BPD的风险增加相关联。高氧诱导新生小鼠肺中NF-κ B活化。然而，导致这种激活和下游效应的机制途径是未知的。该建议的中心假设是，IkB 1，一种NF-κ B抑制蛋白，具有独特的特性，使其在新生儿肺中调节高氧诱导的NF-κ B活化至关重要。具体目标包括：1）确定IkB 1在胎儿和新生小鼠肺中的发育表达谱，2）测试IkB 1特异性NF-κ B活化的非典型途径在调节暴露于高氧的新生小鼠肺损伤中的作用，和3）确定一氧化氮是否抑制NF-κ B活化的非典型途径。通过进一步确定IkB 1的独特特性及其在调节高氧诱导的NF-κ B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。 公共卫生相关性：早产影响所有出生的12%以上，占所有围产期并发症的85%以上。早产使婴儿易患支气管肺发育不良或慢性肺病，每年有10，000至15，000名新生儿患上这种疾病。旨在预防BPD发展的干预措施将减少这一重大公共卫生负担的影响。

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