Resolution of Diffuse Inflammatory Lung Injury in Neonatal Mice

新生小鼠弥漫性炎症性肺损伤的解决

基本信息

批准号：
9769845
负责人：
Sharon Ann McGrath-Morrow
金额：
$ 40.79万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-15 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769845
关键词：
5 year old Acute Lung Injury Adolescent Adoptive Cell Transfers Adoptive Transfer Adult Age Amphiregulin Antibiotics Antigen-Presenting Cells Antigens Attenuated Bacteria Bacterial Pneumonia Biological Response Modifiers CD4 Positive T Lymphocytes Cause of Death Cell Lineage Cells Child Childhood Chronic Obstructive Airway Disease Clinical DNA DNA Methylation DNA Methyltransferase Inhibitor Data Developing Countries Development Diffuse Disease Disease Outcome Epidermal Growth Factor Receptor Epigenetic Process Epithelial Escherichia coli Escherichia coli Infections Exposure to FOXP3 gene Gene Expression Gene Expression Profile Genes Genetic Growth IL2RA gene Immune Immune Response Genes Immune response Impairment Infant Infection Inflammation Inflammatory Inflammatory Response Influenza Influenza A Virus, H1N1 Subtype Interferons Investigation Knockout Mice Lead Life Ligands Long-Term Effects Lower Respiratory Tract Infection Lower respiratory tract structure Lung Lung Inflammation Lung infections Medical Methylation Mind Morbidity - disease rate Mus Neonatal Outcome Pathway interactions Phenotype Pneumonia Public Health Recovery Regulation Regulatory T-Lymphocyte Reporting Resolution Respiratory physiology Risk Role Severity of illness Sex Differences Site T cell response T-Lymphocyte Testing Time Translating Up-Regulation Vaccines Weight Gain age difference age related antimicrobial base cytokine early childhood early life exposure effector T cell genome-wide improved improved outcome inhibitor/antagonist injured insight interleukin-22 lung injury lung repair methylome mortality neonatal immune system neonate pathogen personalized approach promoter repaired respiratory response sex transcriptome sequencing

项目摘要

ABSTRACT Pneumonia is a leading cause of death in children less than 5 years of age and it is the most common cause of mortality in children living in developing countries. Each year there are an estimated 150 million cases of childhood pneumonia worldwide resulting in approximately one million children dying each year. Although vaccines and antibiotics have dramatically improved outcomes in older children with lower respiratory tract infections, infants and young children disproportionately suffer from the highest morbidity and mortality from pneumonia. In addition, the long-term effects of childhood pneumonia can lead to impaired lung function in adult life and increase the risk of developing chronic obstructive lung disease. With these highly significant medical and public health outcomes in mind, there is a need for a more in- depth understanding of the neonate/infant lung immune response to pneumonia. Questions that require further investigation include; identifying mechanisms that regulate age and sex differences in immune responsiveness to lower respiratory tract infections (LRTI), how these variables influence short and long-term outcomes to LRTIs and whether regulators of immune responsiveness in the lung can be altered to attenuate disease severity in the neonate and young child. Thus identifying approaches that can boost the neonatal immune system during lower respiratory tract illnesses could potentially improve outcomes. Our preliminary studies indicate that lung CD4+ T cells in neonates are hypo-responsive to LRT E. coli. Since CD4+ T cells are critically important for host responsiveness to LRTI as evident by genetic and acquired deficiencies, we will focus on regulatory mechanisms that underlie CD4+ T cell responsiveness in neonatal lung. In this proposal, we will build on studies supported by our previous proposal, to examine age-related differences in lung CD4+ T cell responsiveness to E. coli pneumonia. We will examine the role of the DNA methylome in regulating neonatal lung CD4+ T cell responses to pneumonia and determine if DNA methyltransferase inhibitors can disrupt the normal neonatal CD4+ T cell response to LRTI. Finally, we will examine if sex-specific differences in respiratory outcomes to H1N1 in adults are determined by differential methylation of promoter sites in CD4+ T cell genes that are critical to the host response to influenza. In aim 1, we will focus on CD4+ T cell-derived IL-22, IFN, and AREG to determine their role in the lung’s host response to LRTIs in the neonate and juvenile. In aim 2a, we will examine the role of the DNA methylome in regulating CD4+ T cell responsiveness in neonatal and juvenile lung. In aim 2b, we will determine if exposure to LRT E. coli during childhood can alter lung CD4+ T cell responsiveness in a sex-specific manner in adults with influenza, through changes in DNA methylation promoter sites. Together, these studies will provide mechanistic insights into age-related differences in LRTI outcomes and the influence of childhood bacterial exposures on the immune response to lung infections in adults.

抽象的肺炎是不到5岁的儿童死亡的主要原因，这是最常见的居住在发展中国家的儿童死亡原因。每年估计有1.5亿个案件全世界儿童肺炎的肺炎，每年大约有100万儿童死亡。虽然疫苗和抗生素已大大改善了下呼吸道的大儿童感染，婴儿和幼儿的发病率和死亡率最高肺炎。此外，儿童肺炎的长期作用会导致肺功能受损成人生活并增加患慢性阻塞性肺部疾病的风险。考虑到这些非常重要的医学和公共卫生结果，需要更多的信息对新生儿/婴儿肺免疫反应对肺炎的深度理解。需要进一步的问题调查包括；确定调节免疫反应性年龄和性别差异的机制对于下呼吸道感染（LRTI），这些变量如何影响短期和长期结局 LRTI以及是否可以改变肺部免疫响应性调节剂以减轻疾病新生儿和幼儿的严重程度。识别可以增强新生儿免疫的方法下呼吸道疾病期间的系统可能会改善预后。我们的初步研究表明，新生儿中的肺CD4+ T细胞对LRT大肠杆菌无反应。由于CD4+ T细胞对于宿主对LRTI的反应至关重要，如遗传和获得缺陷，我们将重点关注CD4+ T细胞反应性基础的调节机制肺。在此提案中，我们将基于我们以前的提议支持的研究，以检查与年龄有关的肺CD4+ T细胞对大肠杆菌肺炎的反应性差异。我们将检查DNA的作用调节新生儿肺CD4+ T细胞对肺炎的反应中的甲基团，并确定DNA是否甲基转移酶抑制剂会破坏正常的新生儿CD4+ T细胞对LRTI的反应。最后，我们会的检查成人H1N1的呼吸结局的性别特异性差异是否取决于差异 CD4+ T细胞基因中启动子位点的甲基化对宿主对影响的反应至关重要。在AIM 1中，我们将重点关注CD4+ T细胞衍生的IL-22，IFN和AREG，以确定它们在肺部宿主反应中的作用到新生儿和少年中的lrtis。在AIM 2A中，我们将检查DNA甲基在调节中的作用新生儿和青少年肺中的CD4+ T细胞反应性。在AIM 2B中，我们将确定是否暴露于LRT E。儿童时期的大肠杆菌可以在成年人中以性别特异性的方式改变肺CD4+ T细胞反应能力影响力通过DNA甲基化启动子位点的变化。这些研究将共同提供对年龄相关的LRTI结局差异的机理洞察力和儿童期细菌的影响成人对肺部感染的免疫激发暴露。