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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：
10040906
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/10040906
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 Inflammation 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 period neonatal sepsis neonate novel pathogenic bacteria peripheral blood pup 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.

项目总结