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: 10190312
• 负责人: Nicholas J. Bessman
• 金额: $ 17.78万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 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 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190312
• 关键词: Acute; Address; Affect; Anatomy; Anemia; Anemia due to Chronic Disorder; Bacteria; Biological Markers; Biology; Cell physiology; Cells; Cellular biology; Childhood; Chronic; Complication; Crohn' s disease; Data; Dendritic Cells; Diabetes Mellitus; Dietary Iron; Disease; Genetic; Growth; Health; Helicobacter hepaticus; Homeostasis; Hormones; Human; 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; healing; hepcidin; inflammatory disease of the intestine; innovation; iron supplementation; macrophage; metal transporting protein 1; microbiota; mouse model; neutrophil; novel; novel therapeutic intervention; senescence; 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，而铁稳态失调在IBD病理中的作用尚不清楚。 因此，更好地了解肠道铁稳态可能有助于制定新的治疗策略。 IBD和IBD相关性贫血。贫血和炎症由荷尔蒙海普西丁直接联系在一起，这种荷尔蒙 通过铁转运蛋白严重抑制细胞内储存的铁的释放。在新的数据中，我已经 树突状细胞(DC)产生的海普西丁对肠道损伤后的组织修复至关重要 儿童克罗恩病炎症组织中树突状细胞高表达海普西丁 (CD)病人。此外，海普西丁通过限制组织相关细菌的铁供应来促进愈合。 肠道髓系细胞中铁的封存。这项研究建议的重点是调查 在慢性肠炎和慢性肠炎中，肠道铁稳态受海普西丁调节的假设 促进儿科克罗恩病患者组织愈合。在目标1中，我将审问海普西丁和 铁转运蛋白与慢性肠炎、铁稳态和髓系细胞生物学。在目标2中，我将定义 在人类中，海普西丁和铁蛋白表达的调节，我将探索这个轴， 铁稳态和肿瘤坏死因子阻滞剂在儿童克罗恩病中的应用。我将采用创新的技术方法 为了表征小鼠和IBD患者样本中的解剖铁水平，我将开发新的遗传工具来 研究海普西丁和铁蛋白在髓系细胞中的作用。总而言之，这些研究的结果将定义 IBD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。