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Cross-talk between iron metabolism and intestinal inflammation

铁代谢与肠道炎症之间的串扰

基本信息

批准号：
9172845
负责人：
Bobby Joseph Cherayil
金额：
$ 42.03万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9172845
关键词：
Affect Anemia Anemia due to Chronic Disorder Animals Bacteria Binding Blood Circulation Bone Morphogenetic Proteins Cell Culture Techniques Cell membrane Colitis Complication Development Diet Disease Down-Regulation Enterocytes Erythrocyte Aging Erythropoiesis Foundations Funding Gene Expression Genes Goals Grant Hepatic Hepatocyte Homeostasis Hormones In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interleukin-1 beta Interleukin-10 Interleukin-6 Intervention Iron Knockout Mice Knowledge Lead Light Liver Mediating Metagenomics Molecular Nutrient Oral Organism Pathogenesis Piroxicam Play Probiotics Quality of life Recycling Regulation Role STAT3 gene Serum Signal Pathway Signal Transduction Sodium Dextran Sulfate Source Streptomycin System Testing Up-Regulation Wild Type Mouse Work absorption base cytokine effective therapy fecal transplantation follow-up gut microbiota hepcidin in vivo insight interest iron metabolism iron supplement macrophage member metabolomics metagenomic sequencing metal transporting protein 1 microbial community microbiota monocyte mouse model novel novel therapeutic intervention prebiotics prevent research study response tissue culture transcription factor treatment strategy

项目摘要

PROJECT SUMMARY The anemia of inflammation (AI) is a frequent complication of inflammatory bowel disease (IBD) and is caused by abnormally elevated expression of the hepatocyte-derived hormone hepcidin, the central regulator of systemic iron homeostasis. Inflammation-associated increases in hepcidin expression lead to intracellular iron sequestration, hypoferremia and compromised erythropoiesis. Effective treatment of AI requires detailed knowledge of the mechanisms that up-regulate hepcidin in the context of inflammation. The goal of the proposed studies is to elucidate these mechanisms using tissue culture approaches as well as mouse models of IBD. In preliminary in vivo experiments, we have found that gut microbiota composition has a significant influence on hepcidin expression during colitis and that this influence is associated with altered STAT3 activity and STAT3-dependent gene expression in the liver. In addition, we have found from in vitro studies that resident gut bacteria are able to induce the secretion of IL-1β by monocyte-macrophages, and that this cytokine acts on hepatocytes to up-regulate hepcidin by a novel mechanism involving activation of the bone morphogenetic protein (BMP) signaling pathway. Based on our findings, we hypothesize that the gut microbiota has an important, previously unappreciated, effect on hepcidin expression during intestinal inflammation, and that clarifying the molecular basis of this effect may lead to new strategies for manipulating hepcidin levels. We will test this idea in experiments that will characterize 2 mechanisms by which the microbiota influences hepcidin expression: (1) We will follow up on our preliminary in vivo observations to clarify which aspects of STAT3-dependent hepcidin up-regulation are influenced by the microbiota. We will also use metagenomic sequencing and metabolite profiling to shed light on the mechanisms that mediate the effects of the microbiota on hepcidin expression. (2) Following up on our preliminary in vitro findings, we will use a combination of in vitro and in vivo experiments to clarify how resident gut bacteria up-regulate hepcidin via the novel IL-1β-mediated, BMP signaling-dependent mechanism. We will also determine the in vivo role of this mechanism in colitis-associated hepcidin up-regulation. The results of our studies will increase understanding of AI pathogenesis in IBD, and thus facilitate development of new treatments for this problem.

项目总结