Mechanisms of acute bowel injury Role of NF-KB

急性肠损伤的机制 NF-KB 的作用

基本信息

批准号：
7425928
负责人：
Isabelle G De Plaen
金额：
$ 12.91万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7425928
关键词：
Abbreviations Acute Address Animals Antibiotics Attenuated Award Bacteria Binding Biological Factors Bone Marrow Bone Marrow Transplantation Catheters Cell Adhesion Molecules Cells Data Development Diagnostic Disease Disease Progression Down-Regulation Endotoxins Enterocolitis Environment Gene Transfer Germ-Free Goals Human Hypoxia Incidence Infant Inflammation Inflammatory Inflammatory Response Injury Intercellular adhesion molecule 1 Intestines Knowledge Lead Lipopolysaccharides Luciferases Maintenance Mediator of activation protein Mentorship Modeling Molecular Morbidity - disease rate Mus Mutate NF-kappa B Necrosis Necrotizing Enterocolitis Neonatal Neonatal Intensive Care Neonatal Intensive Care Units Neutrophil Infiltration Newborn Infant Nuclear Nucleosome Binding Domain Pathway interactions Peptides Phase Phospholipase A2 Platelet Activating Factor Premature Infant Preparation Prevention Probiotics Proteins Rattus Regulation Regulatory Pathway Reporter Research Research Personnel Risk Factors Role Scientist Small Intestines Staging Sterility Stress TNFRSF5 gene Therapeutic Intervention Tissues Transgenic Mice Transgenic Organisms Tumor Necrosis Factor-alpha Tumor Necrosis Factors Up-Regulation career chemokine cytokine dimer feeding human TNF protein improved in vivo inhibitor/antagonist laser capture microdissection lipid mediator macrophage inflammatory protein 2 mortality mouse model neutrophil novel p65 prevent programs response skills tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is a major concern in the neonatal intensive care unit, causing great morbidity and mortality. My long-term career goal is to elucidate the molecular mechanisms that lead to the development of NEC in the premature newborn infant. This will lead to the prevention and treatment of this devastating disease. My short-term goals are to gain knowledge and novel technical skills (such as in vivo gene transfer and laser-capture microdissection) that will enable me to make significant contributions in the field of NEC research and to become an independent research scientist. This award would allow the necessary support to achieve these goals, under the mentorship of Dr. Michael Caplan and Dr. Terrence Barrett in an excellent research environment. We have preliminary evidence that the transcription factor nuclear factor- (NF-kB) is developmentally regulated in the intestine and is persistently activated in a neonatal rat model of NEC. My overall hypothesis is that NEC results from the prolonged activation of NF- kB in the premature intestine in response to bacterial products and locally produced inflammatory lipid mediators such as platelet-activating factor (PAF), causing neutrophil infiltration and necrosis. In the premature infant, this persistent NF-kB activation leads to the upregulation of pro-inflammatory cytokines (e.g. TNF), chemokines (e.g. MIP-2) and adhesion molecules (e.g. ICAM-1) which amplify the inflammatory response. As a result, neutrophils are mobilized and activated, causing irreversible tissue injury and necrosis. The following specific aims will be addressed: 1) to characterize NF-kB activation in the neonatal model of NEC induced by hypoxia-cold stress-formula feeding; 2) to study the role of NF-kB in the neonatal NEC model and its mechanisms of action in a model of acute bowel injury; 3) to examine the effect of modulating the intestinal flora and treatment with probiotics on intestinal NF-KB activation in the neonatal NEC model. To do so, several transgenic mice models are proposed: mice lacking or over-expressing a specific subunit of NF-kB, reporter mice expressing NF-kB-dependent luciferase and finally in vivo gene transfer will be used. Understanding the developmental differences in the NF-kB activating pathway might lead to specific strategies geared at inhibiting NF-kB activation in the early stages of necrotizingenterocolitis. This could prevent its progression toward irreversible intestinal damage and improve the survival of premature infants.

描述（由申请人提供）：坏死性小肠结肠炎（NEC）是新生儿重症监护病房的一个主要问题，导致很高的发病率和死亡率。我的长期职业目标是阐明导致早产儿 NEC 发生的分子机制。这将有助于预防和治疗这种毁灭性疾病。我的短期目标是获得知识和新颖的技术技能（例如体内基因转移和激光捕获显微切割），这将使我能够在 NEC 研究领域做出重大贡献并成为一名独立研究科学家。该奖项将为在迈克尔·卡普兰博士和泰伦斯·巴雷特博士的指导下在良好的研究环境中实现这些目标提供必要的支持。我们有初步证据表明转录因子核因子（NF-kB）在肠道中受到发育调节，并且在 NEC 新生大鼠模型中持续激活。我的总体假设是，NEC 是由于细菌产物和局部产生的炎症脂质介质（例如血小板激活因子 (PAF)）对早产肠道中 NF-kB 的长期激活造成的，导致中性粒细胞浸润和坏死。在早产儿中，这种持续的 NF-kB 激活导致促炎细胞因子（例如 TNF）、趋化因子（例如 MIP-2）和粘附分子（例如 ICAM-1）的上调，从而放大炎症反应。结果，中性粒细胞被动员和激活，导致不可逆的组织损伤和坏死。将解决以下具体目标：1）表征缺氧冷应激配方喂养诱导的 NEC 新生儿模型中 NF-kB 激活的特征； 2）研究NF-kB在新生儿NEC模型中的作用及其在急性肠损伤模型中的作用机制； 3) 在新生儿NEC模型中研究调节肠道菌群和益生菌治疗对肠道NF-KB激活的影响。为此，提出了几种转基因小鼠模型：缺乏或过度表达 NF-kB 特定亚基的小鼠，表达 NF-kB 依赖性荧光素酶的报告小鼠，最后将使用体内基因转移。了解 NF-kB 激活途径的发育差异可能会导致在坏死性小肠结肠炎早期阶段抑制 NF-kB 激活的具体策略。这可以防止其发展为不可逆的肠道损伤，并提高早产儿的存活率。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of nuclear factor-kappaB ameliorates bowel injury and prolongs survival in a neonatal rat model of necrotizing enterocolitis.

抑制核因子-κB 可改善新生大鼠坏死性小肠结肠炎模型的肠损伤并延长其生存期。

DOI：
发表时间：
2007-06
期刊：
影响因子：
3.6
作者：
De Plaen, Isabelle G;Liu, Shirley X L;Tian, Runlan;Neequaye, Isaac;May, Michael J;Han, Xin;Hsueh, Wei;Jilling, Tamas;Lu, Jing;Caplan, Michael S
通讯作者：
Caplan, Michael S

Characterization of a necrotizing enterocolitis model in newborn mice.

新生小鼠坏死性小肠结肠炎模型的表征。

DOI：
发表时间：
2010-09-21
期刊：
International journal of clinical and experimental medicine
影响因子：
0
作者：
Runlan Tian;S. Liu;Cara E. Williams;Thomas D. Soltau;R. Dimmitt;Xiaotian Zheng;Isabelle G. De Plaen
通讯作者：
Isabelle G. De Plaen

Lipopolysaccharide induces CXCL2/macrophage inflammatory protein-2 gene expression in enterocytes via NF-kappaB activation: independence from endogenous TNF-alpha and platelet-activating factor.

脂多糖通过 NF-κB 激活诱导肠细胞中 CXCL2/巨噬细胞炎症蛋白 2 基因表达：独立于内源性 TNF-α 和血小板激活因子。