权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9613428
负责人：
Sharon Ann McGrath-Morrow
金额：
$ 42.38万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9613428
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 Effector Cell 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 Characteristics 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 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.

摘要