The role of local iron homeostasis in inflammatory bowel disease

局部铁稳态在炎症性肠病中的作用

• 批准号: 10463877
• 负责人: Nicholas J. Bessman
• 金额: $ 17.63万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463877
• 关键词: Acute; Address; Affect; Anatomy; Anemia; Anemia due to Chronic Disorder; Bacteria; Biological Markers; Biology; Cell physiology; Cells; Cellular biology; Childhood; Chronic; Colitis; Complication; Crohn' s disease; Data; Dendritic Cells; Diabetes Mellitus; Dietary Iron; Disease; Genetic; Growth; Health; Helicobacter hepaticus; Homeostasis; Hormones; Human; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Iron; Knowledge; Link; Liver Cirrhosis; Malignant neoplasm of liver; Mammals; Mediating; Microbe; Mucous Membrane; Mus; Myeloid Cells; Pathology; Patient risk; Patients; Pediatric Crohn' s disease; Personal Satisfaction; Phagocytes; Predisposition; Publishing; Recycling; Refractory; Regulation; Research Proposals; Resistance; Role; Sampling; Small Intestines; Sodium Dextran Sulfate; Sum; T-Lymphocyte; TNF gene; Therapeutic; Tissues; Variant; Work; cell type; experience; extracellular; gut inflammation; healing; hepcidin; innovation; iron supplementation; macrophage; metal transporting protein 1; microbiota; mouse model; neutrophil; novel; novel therapeutic intervention; senescence; standard care; therapeutic target; tissue repair; tool; uptake

PROJECT ABSTRACT Anemia is the most common complication of inflammatory bowel disease (IBD). IBD-associated anemia is often refractory to treatment, and the role of dysregulated iron homeostasis in IBD pathology is unknown. Accordingly, a better understanding of intestinal iron homeostasis may facilitate new therapeutic strategies for IBD and IBD-associated anemia. Anemia and inflammation are directly linked by the hormone hepcidin, which critically inhibits iron release from intracellular stores via the iron transporter ferroportin. In new data, I've identified that hepcidin produced by dendritic cells (DCs) is critical for tissue healing after intestinal inflammation, and that hepcidin is highly expressed by DCs in inflamed tissues of pediatric Crohn's disease (CD) patients. Moreover, hepcidin promoted healing by limiting iron availability to tissue-associated bacteria via iron sequestration in intestinal myeloid cells. The focus of this research proposal is to investigate the hypothesis that intestinal iron homeostasis is regulated by hepcidin in chronic intestinal inflammation and in pediatric Crohn's patients to promote tissue healing. In Aim 1, I will interrogate the role of hepcidin and ferroportin in chronic intestinal inflammation, iron homeostasis, and myeloid cell biology. In Aim 2, I will define the regulation of hepcidin and ferroportin expression in humans, and I will probe correlations between this axis, iron homeostasis, and TNF blockers in pediatric Crohn's disease. I will employ innovative technical approaches to characterize anatomical iron levels in mice and IBD patient samples, and I will develop new genetic tools to study the role of hepcidin and ferroportin in myeloid cells. Collectively, results from these studies will define the regulation and functional significance of intestinal iron homeostasis in IBD, with the potential to define novel therapeutic strategies for pediatric CD patients.

项目摘要 贫血是炎症性肠病（IBD）最常见的并发症。IBD相关性贫血是 通常难以治疗，并且铁稳态失调在IBD病理学中的作用尚不清楚。 因此，更好地了解肠道铁稳态可能有助于新的治疗策略， IBD和IBD相关性贫血。贫血和炎症与铁调素激素直接相关， 通过铁转运体膜铁转运蛋白严重抑制铁从细胞内储存释放。在新的数据中， 确定了由树突状细胞（DC）产生的铁调素对于肠内感染后的组织愈合至关重要， 炎症，并且铁调素在小儿克罗恩病的发炎组织中由DC高度表达 (CD)患者此外，铁调素通过限制组织相关细菌的铁可用性来促进愈合， 铁螯合在肠骨髓细胞。本研究计划的重点是调查 铁调素在慢性肠道炎症和慢性炎症中调节肠铁稳态假说 以促进组织愈合。在目标1中，我将询问hepcidin的作用， 铁转运蛋白在慢性肠道炎症、铁稳态和骨髓细胞生物学中的作用。在目标2中，我定义 人类铁调素和铁转运蛋白表达的调节，我将探索这个轴之间的相关性， 铁稳态和TNF阻滞剂在小儿克罗恩病中的应用。我将采用创新的技术方法 来表征小鼠和IBD患者样本中的解剖铁水平，我将开发新的遗传工具， 研究铁调素和铁转运蛋白在骨髓细胞中的作用。总的来说，这些研究的结果将定义 IBD患者肠道铁稳态的调节和功能意义，有可能定义新的 儿童CD患者的治疗策略。