The regulation of early life interleukin-27 expression and metabolic impact

生命早期 IL-27 表达的调节和代谢影响

基本信息

批准号：
10171779
负责人：
Cory Michael Robinson
金额：
$ 7.6万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171779
关键词：
Address Adipose tissue Adult Bacteria Biology Blood Blood Glucose Cells Cessation of life Child Choline DNA Methylation DNA Methylation Regulation DNA Sequence Development Epigenetic Process Event Exhibits Gene Expression Genes Glucose Human Hypoglycemia IL27RA gene Immune Immune Targeting Immune response Immune system Immunity Immunologics Infant Mortality Infection Inflammatory Response Interleukins Knowledge Laboratories Life Link Liver Low Birth Weight Infant Measures Metabolic Methionine Methylation Modeling Mus Myeloid-derived suppressor cells Neonatal Newborn Animals Newborn Infant Older Population Pancreas Pathway interactions Peripheral Phase Population Predisposition Production Regulation Reporting Research Risk Risk Factors Sepsis Serum Shapes Signal Transduction Skeletal Muscle Source Testing Time Tissues Transcript Translating Umbilical Cord Blood Vaccination Vulnerable Populations Weight Gain Work age group age related bisulfite sequencing blood glucose regulation cell type cohort cytokine early detection biomarkers early onset epigenetic regulation high risk immunological intervention improved improved outcome infection risk macrophage methyl group microbial mortality mortality risk mouse model neonatal human neonatal mice neonatal period neonatal sepsis neonate novel pathogenic bacteria peripheral blood pup systemic inflammatory response transcriptome transcriptome sequencing

项目摘要

PROJECT SUMMARY Microbial infections are a major cause of infant mortality worldwide. For particularly vulnerable populations such as pre-term and low birth weight babies, the risk of invasive infections further escalates. The neonatal period is defined by a distinct or immature immune system, and many features of a protective host response to infection are deficient as compared with older children and adults. Our laboratory has identified that expression of the immune suppressive cytokine interleukin (IL)-27 is elevated in human and murine neonates. Other recent studies have shown IL-27 to be a biomarker for early onset neonatal sepsis. This suggests that elevated IL-27 may represent a risk factor and when further increased during bacterial challenge, compromise the host immune response. We have shown that macrophages and myeloid-derived suppressor cells (MDSCs) are the dominant sources of elevated IL-27 in the neonatal phase and their contributions manifest as elevated levels of serum IL-27 compared with older populations. Cumulatively, this points to IL-27 as a host molecule that represents a target for immune intervention to improve the host response and reduce susceptibility to infection early in life. We present strong evidence in a mouse model that the absence of IL-27 signaling translates to improved survival, better weight gain, and enhanced clearance of bacteria during neonatal sepsis. In the current proposal, we seek to understand the regulation of elevated levels of early life IL-27 and the functional consequence to neonates during infection. A deeper understanding of these aspects of IL-27 biology will help to inform targeted approaches to mitigate IL-27-regulated deficiencies in the host response to infection. In the first aim we explore the hypothesis that IL-27 genes are hypomethylated in neonates allowing for increased expression that is reduced in adults by methylation. In the second aim we investigate the hypothesis that IL-27 contributes to the regulation of glucose homeostasis. This hypothesis is derived from the observation in our murine sepsis model, that IL-27 receptor-deficient neonates resist hypoglycemia that develops during neonatal sepsis. The transcriptome will be examined in tissues from wild-type and IL-27 receptor-deficient neonatal pups in the presence and absence of infection. At the completion of this project, we expect to have an enhanced understanding of regulatory mechanisms that contribute to differential IL-27 expression early in life and uncovered a novel link between host immunity and glucose homeostasis. These findings will have translational value and the potential to improve outcomes in human neonates.

项目概要微生物感染是全世界婴儿死亡的主要原因。对于特别脆弱的人群例如早产儿和低出生体重儿，侵袭性感染的风险进一步上升。新生儿时期是由独特的或不成熟的免疫系统以及保护性宿主反应的许多特征来定义的与年龄较大的儿童和成人相比，感染率较低。我们的实验室已经鉴定出这种表达免疫抑制细胞因子白细胞介素 (IL)-27 在人类和小鼠新生儿中升高。其他最近的研究表明 IL-27 是早发新生儿败血症的生物标志物。这表明升高 IL-27 可能是一种危险因素，当在细菌攻击过程中进一步增加时，会对宿主造成损害免疫反应。我们已经证明巨噬细胞和骨髓源性抑制细胞（MDSC）是新生儿期 IL-27 升高的主要来源及其贡献表现为 IL-27 水平升高与老年人群相比，血清 IL-27 水平更高。总的来说，这表明 IL-27 作为宿主分子代表免疫干预的目标，以改善宿主反应并降低感染易感性在生命的早期。我们在小鼠模型中提供了强有力的证据，表明 IL-27 信号传导的缺失会转化为提高新生儿败血症期间的生存率、增加体重并增强细菌清除率。在目前的提案中，我们试图了解早期生命 IL-27 水平升高的调节以及功能性感染期间对新生儿的影响。更深入地了解 IL-27 生物学的这些方面将有助于为缓解宿主对感染反应中 IL-27 调节缺陷的有针对性的方法提供信息。在我们的第一个目标是探讨新生儿 IL-27 基因低甲基化的假设，从而增加成人中的表达因甲基化而降低。在第二个目标中，我们研究了 IL-27 的假设有助于葡萄糖稳态的调节。这个假设源自我们的观察鼠败血症模型，IL-27 受体缺陷的新生儿可以抵抗新生儿期发生的低血糖败血症。将在野生型和 IL-27 受体缺陷型新生儿的组织中检查转录组幼犬是否存在感染。在该项目完成后，我们预计将有一个增强对生命早期 IL-27 差异表达调节机制的理解并发现了宿主免疫和葡萄糖稳态之间的新联系。这些发现将有转化价值和改善人类新生儿结局的潜力。