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Aryl hydrocarbon receptor signaling in the pathogenesis of necrotizing enterocolitis

坏死性小肠结肠炎发病机制中的芳基烃受体信号传导

基本信息

批准号：
9220912
负责人：
MISTY L GOOD
金额：
$ 7.63万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9220912
关键词：
Adult Affect Anti-Inflammatory Agents Anti-inflammatory Apoptosis Aryl Hydrocarbon Receptor Attenuated Award Breast Feeding CD4 Positive T Lymphocytes Cell Culture Techniques Cell Proliferation Cell Separation Cells Clinical Data Development Diet Diet Modification Disease Endotoxemia Enteral Enterocytes Epithelial Flow Cytometry Formula supplementation Future Gastrointestinal Diseases Goals Growth Histology Homeostasis Host Defense Host Defense Mechanism Human Human Milk Hypoxia Immunohistochemistry Infant Infant Mortality Infant formula Inflammatory Inflammatory Response Inflammatory disease of the intestine Interleukin Receptor Interleukin-17 Intestines Knowledge Lymphoid Cell Mediating Modeling Mucosal Immunity Mus Natural Immunity Natural regeneration Necrosis Necrotizing Enterocolitis Neonatal Nutritional Organ failure Outcome Pathogenesis Pathogenicity Play Premature Infant Prevention strategy Production Property Prophylactic treatment Quantitative Reverse Transcriptase PCR Receptor Signaling Recombinant Interleukins Research Role Severities Signal Pathway Signal Transduction Stem cells Survival Rate T-Lymphocyte Testing Therapeutic United States United States National Institutes of Health Wound Healing aryl hydrocarbon receptor ligand base cell type cytokine defense response design high risk interleukin-22 intestinal epithelium intestinal homeostasis mortality mouse model novel nutritional supplementation prevent response therapeutic target

项目摘要

Abstract Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease affecting up to 10% of premature infants and characterized by an interleukin (IL)-17-driven uncontrolled inflammatory response. The goals of the proposed research are to identify the innate host defense responses in NEC pathogenesis and interrogate how these responses can be modified or prevented through dietary modifications. We have shown that breast milk mediates protection against NEC by inhibiting the pro-inflammatory signaling in the intestinal epithelium and we seek to determine the components of breast milk that mediate this anti-inflammatory effect. We now show that breast milk contains anti-inflammatory aryl hydrocarbon receptor (AhR) ligands, which have been shown to be critical for maintaining gut homeostasis by inducing expansion of innate lymphoid cells (ILC) and protective T helper (Th22) cells via IL-22 production. IL-22 signaling plays a critical role in attenuating intestinal inflammation, gut barrier function and promoting wound healing by facilitating intestinal stem cell regeneration. Importantly, these findings highlight the therapeutic potential of enhancing IL-22 production to attenuate pro- inflammatory responses seen in NEC. Therefore, we hypothesize that IL-22 producing cells play a protective role in NEC and that nutritional supplementation with AhR ligands will naturally induce intestinal IL-22 production, and inhibit the pathogenic IL-17 responses seen in NEC. To test this hypothesis, we will use our experimental NEC model and an ex vivo model of intestinal stem cell isolation and culture to pursue the following specific aims: Aim 1: To investigate the role of IL-22 producing cells in NEC pathogenesis. Aim 2: To determine the role of AhR signaling in NEC pathogenesis. These studies will advance our understanding of the signaling pathways involved in the pathogenesis of NEC and test the novel preventative nutritional strategy of manipulating anti-inflammatory cytokine production with dietary AhR ligands.

摘要