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：
9301440
负责人：
Bobby Joseph Cherayil
金额：
$ 45.77万
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/9301440
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 Duodenum Enterocytes Erythrocytes Erythropoiesis Foundations Funding Gene Expression Genes Goals Grant Hepatic Hepatocyte Homeostasis Hormones Impairment 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 Regulation Role STAT3 gene Serum Signal Pathway Signaling Protein Sodium Dextran Sulfate Source Streptomycin System Testing Up-Regulation Wild Type Mouse Work absorption aged base cytokine effective therapy experimental study 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 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.

项目概要炎症性贫血（AI）是炎症性肠病（IBD）的常见并发症，是由肝细胞源性激素铁调素（hepcidin）的表达异常升高，铁调素是肝细胞的中枢调节因子炎症相关的铁调素表达增加导致细胞内铁的全身铁稳态。隔离、低铁血症和红细胞生成受损需要详细的治疗。了解在炎症情况下上调铁调素的机制。拟议的研究是利用组织培养方法和小鼠模型来阐明这些机制在初步的体内实验中，我们发现肠道微生物群的组成对 IBD 具有显着的影响。对结肠炎期间铁调素表达的影响，并且这种影响与 STAT3 活性相关此外，我们从体外研究中发现，肝脏中STAT3依赖性基因表达。常驻肠道细菌能够诱导单核巨噬细胞分泌 IL-1β 细胞因子作用于肝细胞，通过涉及骨活化的新机制上调铁调素根据我们的研究结果，我们发现肠道中存在形态发生蛋白（BMP）信号通路。肠道微生物群对铁调素表达具有重要的、以前未被认识到的影响炎症，阐明这种效应的分子基础可能会带来操纵炎症的新策略我们将在实验中测试这个想法，该实验将描述铁调素水平的两种机制。微生物群影响铁调素表达：（1）我们将跟进我们的初步体内观察我们将澄清 STAT3 依赖性铁调素上调的哪些方面受到微生物群的影响。还使用宏基因组测序和代谢物分析来阐明介导的机制 (2) 根据我们的初步体外研究结果，我们将结合体外和体内实验来阐明常驻肠道细菌如何上调铁调素通过新型 IL-1β 介导的、BMP 信号依赖机制，我们还将确定其体内作用。我们的研究结果将增加这种机制与结肠炎相关的铁调素的上调。了解 IBD 中的 AI 发病机制，从而促进针对该问题的新疗法的开发。