Translational Regulation of Gene Expression in Neonatal PMNs

新生儿 PMN 基因表达的翻译调控

• 批准号: 7795973
• 负责人: CHRISTIAN CON YOST
• 金额: $ 13.45万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795973
• 关键词: Abdomen; Acute; Address; Adult; Area; Binding; CD34 gene; Cells; Cessation of life; Chronic lung disease; Containment; Data; Disease; Fright; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Translation; Hematopoietic stem cells; Human; Infant; Infection; Inflammatory; Inflammatory Response; Interleukin 6 Receptor; Interleukin-6 Receptor Alpha Subunit; Investigation; Lead; Leukocytes; Messenger RNA; Modeling; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Phospholipids; Platelet Activating Factor; Premature Infant; Prevention; Process; Protein Biosynthesis; Proteins; Reaction; Regulation; Regulatory Pathway; Retinoic Acid Receptor; Sepsis; Signal Pathway; Signal Transduction; Sirolimus; Structure; Time; Tissues; Transcript; Translational Regulation; Translations; Umbilical Cord Blood; Untranslated Regions; base; cell type; common treatment; disorder risk; insight; mTOR protein; microbial; model development; neutrophil; platelet activating factor receptor; premature; protein expression; research study; response; transcription factor; wound

DESCRIPTION (provided by applicant): Infants born prematurely are at risk for diseases resulting from dysregulation of the acute inflammatory response such as chronic lung disease, overwhelming sepsis and necrotizing enterocolitis (NEC). NEC is a disease of infants born prematurely that commonly leads to significant morbidity or death. While its pathogenesis remains unknown, dysregulation of the acute inflammatory response is implicated. The polymorphonuclear leukocyte (PMN) responds to tissue damage or microbial infection, accomplishing wound surveillance and bacterial containment. The aim of this project is to elucidate regulatory mechanisms governing the PMN response in the acute inflammatory reaction. In adult PMNs, the mammalian target of rapamycin (mTOR) pathway regulates translation of mRNA transcripts with specific 5'- UTR structures. For platelet activating factor (PAF)-stimulated PMNs, translation of interleukin - 6 receptor a (IL-6Ra) and retinoic acid receptor a (RARa) mRNA transcripts is regulated in this manner. Little however, is known regarding the mTOR pathway in neonatal PMNs isolated from healthy term infants or infants born prematurely. We will isolate PMNs from the cord blood of both term and preterm infants and stimulate them with PAF. We will determine both protein expression and phosphorylative activity for each of the components of the mTOR pathway in both cell types. We will then compare the protein expression of both IL-6Ra and RARa in both cell types to their protein expression in adult PMNs. We will also compare IL-6Ra and RARa expression in the PMNs observed in tissue sections of premature infants with NEC to those of infants undergoing abdominal surgery for reasons other than NEC. Finally, we will develop a human PMN development model, differentiating CD34+ hematopoietic stem cells along the granulocytic lineage. Results of these experiments will provide new and important mechanistic insight into the pathogenesis of NEC, and may lead to improvements in the prevention and treatment of this common and often devastating disease of prematurity.

描述（由申请人提供）：过早出生的婴儿因急性炎症反应失调引起的疾病风险，例如慢性肺部疾病，压倒性败血症和坏死性小肠结肠炎（NEC）。 NEC是一种过早出生的婴儿的疾病，通常会导致大量发病或死亡。尽管其发病机理仍然未知，但涉及急性炎症反应的失调。多形核白细胞（PMN）应对组织损伤或微生物感染，完成伤口监测和细菌抑制。该项目的目的是阐明急性炎症反应中PMN反应的调节机制。在成年PMN中，雷帕霉素（MTOR）途径的哺乳动物靶标调节具有特定5'- UTR结构的mRNA转录物的翻译。对于血小板激活因子（PAF）刺激的PMN，白介素的翻译-6受体A（IL-6RA）和视黄酸受体A（RARA）mRNA转录本以这种方式调节。然而，关于从健康的婴儿或婴儿过早出生的新生儿PMN中的MTOR途径知之甚少。 我们将从术语和早产儿的脐带血中分离PMN，并用PAF刺激它们。 我们将确定两种细胞类型中MTOR途径的每个成分的蛋白质表达和磷酸化活性。然后，我们将比较两种细胞类型的IL-6RA和RARA的蛋白质表达与成人PMN中的蛋白质表达。我们还将比较出于NEC以外的其他原因，在早产儿的组织切片中观察到的PMN中的IL-6RA和RARA表达与接受腹部手术的婴儿的PMN。最后，我们将开发一个人类PMN发展模型，从而区分沿粒细胞谱系的CD34+造血干细胞。这些实验的结果将为NEC的发病机理提供新的和重要的机械洞察力，并可能导致预防和治疗这种常见和经常毁灭性的早产疾病的改善。

项目成果

Deficient Neutrophil Extracellular Trap Formation in Patients Undergoing Bone Marrow Transplantation.

接受骨髓移植的患者中性粒细胞胞外陷阱形成缺陷。

• DOI: 10.3389/fimmu.2016.00250
• 发表时间: 2016
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Glenn,JaredW;Cody,MarkJ;McManus,MeghannP;Pulsipher,MichaelA;Schiffman,JoshuaD;Yost,ChristianCon
• 通讯作者: Yost,ChristianCon

Elevated fecal calprotectin levels during necrotizing enterocolitis are associated with activated neutrophils extruding neutrophil extracellular traps.

• DOI: 10.1038/jp.2016.105
• 发表时间: 2016-10
• 期刊: JOURNAL OF PERINATOLOGY
• 影响因子: 2.9
• 作者: MacQueen, B. C.;Christensen, R. D.;Yost, C. C.;Lambert, D. K.;Baer, V. L.;Sheffield, M. J.;Gordon, P. V.;Cody, M. J.;Gerday, E.;Schlaberg, R.;Lowe, J.;Shepherd, J. G.
• 通讯作者: Shepherd, J. G.